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1
CASCIANO, FABIO. « Aspetti immunologici di pazienti pediatrici con immunodeficienze primitive ». Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2010. http://hdl.handle.net/2108/1278.
Texte intégralRésumé :
La sindrome di DiGeorge (DGS) è causata da una delezione in emizigosi del locus 22q11.2 responsabile di difetti embriogenetici che determinano l’alterazione del timo e delle ghiandole paratiroidee, difetti cardiaci e anomalie facciali caratteristiche. In molti pazienti affetti da questa sindrome, il difetto immunitario è principalmente del compartimento T, sebbene siano state riportate anche anomalie quali disgammaglobulinemia, deficit di IgA e di cellule B della memoria. Sulla base dei dati immunologici, i pazienti DGS sono classificati in DGS completi (cDGS) e DGS parziali (pDGS): i cDGS corrispondono ad una rara forma di immunodeficienza grave combinata (0,5-1%), mentre i pDGS presentano una forma variabile di linfopenia T (da leggera a moderata). Dal punto di vista clinico, questi pazienti mostrano un ampio spettro d’infezioni insieme ad una disregolazione del sistema immunitario con manifestazioni atopiche e autoimmunitarie. I livelli cellulari T, sebbene ridotti, non sono predittivi del rischio di infezioni o autoimmunità.
Le alterazioni della distribuzione del repertorio del recettore delle cellule T (TCR) e il ridotto apporto timico nei pazienti pDGS è stato variabilmente associato ad un maggior rischio di infezioni o autoimmunità.
Per meglio definire alcuni aspetti della patogenesi e delle caratteristiche immunologiche, abbiamo studiato la cinetica della ricostituzione immunologica in una coorte di pazienti pDGS e in pazienti affetti da altre immunodeficienze primitive non direttamente riconducibili ad alterazioni del compartimento di cellule T (come pazienti con Malattia Granulomatosa Cronica - CGD). A tal fine sono state analizzate le cellule mononucleate del sangue periferico valutando:
1. Il fenotipo e le funzioni immunologiche tramite tecniche convenzionali.
2. La distribuzione del repertorio del TCR dei compartimenti cellulari T CD4+ e T CD8+ (TCRBV spectratyping).
3. L’immunofenotipo di maturazione delle cellule B.
4. La frequenza delle cellule nTreg.
La correlazione tra il profilo immunologico in vitro e le caratteristiche cliniche può aiutare a chiarire alcuni aspetti della patogenesi e del difetto immunologico, al fine di identificare dei possibili indicatori di suscettibilità verso le infezioni o verso lo sviluppo di autoimmunità.
Risultati e Discussione: I pazienti pDGS mostravano un ridotto numero di cellule T, sebbene non sia stata trovata una correlazione tra i bassi valori di cellule T e le infezioni ricorrenti. Il numero totale di cellule B nei pazienti pDGS e CGD era normale, sebbene sia stato osservato un significativo decremento di cellule B della memoria. La frequenza delle cellule T regolatorie naturali dei pazienti non mostrava differenze se confrontata con i valori dei controlli sani di pari età.
La risposta linfoproliferativa verso ogni stimolo era statisticamente diminuita in tutti i pazienti.
La distribuzione delle famiglie dei TCRBV è risultata perturbata, con maggiore rilevanza nelle cellule T CD8+ sia nei pazienti pDGS che in quelli CGD. In particolare, l’alterazione delle famiglie TCRBV ha mostrato una tendenza di normalizzazione nella distribuzione del repertorio delle cellule T (sia CD4+ che CD8+), come osservato anche in pazienti infetti da CMV. Le infezioni ricorrenti correlavano con una maggiore frequenza di alterazioni delle famiglie TCRBV nei pazienti pDGS ma non nei pazienti CGD.
Sebbene nella sindrome DiGeorge i bassi valori di cellule T non siano predittivi delle infezioni, le maggiori alterazioni delle famiglie TCRBV, così come l’immunodeficienza umorale e la ridotta frequenza di cellule B della memoria CD27+, risultavano essere associati a un maggiore rischio di infezioni in questi pazienti.
L’analisi dei pazienti CGD ha mostrato delle alterazioni significative sia nel compartimento cellulare T che in quello B, suggerendo che le alterazioni quantitative e qualitative trovate, possono contribuire alla eterogeneità del fenotipo clinico.
Ulteriori studi sono necessari per delucidare come il sistema della NADPH ossidasi è coinvolto nell’alterazione immunologica dei pazienti CGD.
In conclusione, le nostre analisi nelle PID hanno rilevato che altri compartimenti cellulari, oltre a quelli noti, possono essere coinvolti in queste malattie. Pertanto alcuni parametri come la distribuzione delle famiglie del TCRBV e la valutazione della maturazione delle cellule B dovrebbero essere usati come indicatori prognostici del rischio d’infezioni nel corso del follow-up per intraprendere eventuali terapie specifiche.DiGeorge syndrome (DGS) is caused by a deletion in hemizygosis of 22q11.2 locus responsible for embryogenesis defects causing alterations of thymus and parathyroid glands, cardiac defects and abnormal facial features. In most patients, the immune defect is basically in T cell subset although abnormalities such as dysgammaglobulinemia, IgA and memory B cells deficiency have been also reported. On the basis of the immunologic findings, DGS patients are divided in complete DGS (cDGS), a rare form of severe combined immune deficiency (0.5-1%), and partial DGS (pDGS) presenting mild/moderate T cell lymphopenia. Clinically, these patients display a wide spectrum of infections together with a dysregulation of immune system as atopic and autoimmune manifestations. T cell levels, although reduced, are not predictive of the risk to develop infections or autoimmunity. The alterations of the T cell receptor (TCR) repertoire distribution and impaired thymic output in pDGS have been variably associated to a higher risk of infections or autoimmunity. In order to better define some aspects of the pathogenesis and immunological features we studied the kinetic of immune reconstitution in a cohort of pDGS patients and in patients affected by other primary immunodeficiencies not directly affecting T-cell compartments (as Chronic Granulomatous Disease patients) through peripheral blood mononuclear cells (PBMC) analysis of: 1. Phenotype and immunologic functions through standard techniques. 2. TCR repertoire distribution of T CD4+ and T CD8+ subsets (TCRVB spectratyping). 3. Immunophenotypic B-cell maturation. 4. Frequency of T regulatory cells. The correlation between the in vitro immunological profile and the clinical features might help to clarify some aspects of the pathogenesis of the immunological defects, in order to identify possible prognostic markers of increased risk of susceptibility to infections or of development of autoimmunity. Results and Discussion: pDGS patients exhibited decreased T-cell numbers, although no correlation was found between low T-cell values and recurrent infections. Total B-cell numbers in pDGS and CGD patients were normal, although a significantly decreased proportion of memory B cells was observed. No difference in natural T regulatory cells frequency was evident when compared with healthy controls in any groups. A statistical reduced lymphoproliferative response to stimuli (PHA, OKT3 and PWM) in all patients was observed. TCRBV family distribution resulted perturbed, with higher degree in CD8+ T-cell subset in both CGD and pDGS patients. Particularly, TCRBV family alterations in pDGS patients showed a trend of normalization in T cell repertoire distribution (both CD4+ and CD8+ T-cell), as observed in CMV congenital infected patients. Recurrent infections correlated with a high frequency of TCRBV family alterations in pDGS but not in CGD patients. Although low T-cell values were not predictive of recurrent infections in DiGeorge syndrome, higher TCRBV family alterations, as well as humoral immunodeficiency and reduced CD27+ B cell memory frequency, were associated to an increased risk of infections in these patients. Interestingly analysis of CGD patients showed significative alterations in both T and B cells compartments, suggesting that quantitative and qualitative alterations found, might contribute to the heterogeneity in the clinical phenotype. Further studies are needed to elucidate how NADPH oxidase system is involved in CGD patients immune alterations. In conclusion, our analysis on PID patients with well known defective cell compartments revealed that other subsets were also involved, therefore some parameters such as TCRBV family distribution and B-cell maturation could be used as further prognostic markers for follow-up and specific treatment.
2
JACOB, AURELIEN MARC FLORENT. « IMPROVING TARGETED GENE EDITING IN HEMATOPOIETIC STEM CELLS FOR CLINICAL TRANSLATION ». Doctoral thesis, Università degli Studi di Milano-Bicocca, 2021. http://hdl.handle.net/10281/304800.
Texte intégralRésumé :
Negli ultimi anni, l’editing genetico nelle cellule staminali/progenitrici ematopoietiche umane (HSPC) per il trattamento di malattie genetiche del sangue è migliorato drasticamente trasformando inserzioni genetiche casuali in precise e mirate modificazioni del genoma. La modifica mirata dei geni mutati ereditati consente la correzione in situ e la ricostituzione funzionale con il mantenimento del controllo endogeno dell'espressione. Recentemente abbiamo dimostrato che sia le rotture del DNA a doppio filamento indotte dall’editing che il genoma stesso dell’Adeno-Associated Virus 6 (AAV) innescano una risposta dipendente da p53 nell'HSPC che risulta in un ritardo della proliferazione con conseguente diminuzione della ricostituzione ematopoietica dopo il trapianto delle cellule editate in animali immuno-compromessi. Per cui, abbiamo quindi dimostrato come la soppressione di questa risposta mediante l’espressione transitoria della forma negativa dominante di p53 preservi la ricostituzione del lineage ematopoietico. Tuttavia, la biologia sottostante è rimasta sconosciuta, così come l'impatto dell'editing genetico sulle dinamiche clonali dell'HSPC modificate con riparo diretto per omologia (Homology Directed Repair, HDR) al momento del trapianto. Inoltre, lo stato quiescente delle HSC primitive costituisce un limite per l’editing genetico mediato da HDR, riducendo le sue possibili applicazioni cliniche. In questo lavoro, abbiamo prima superato tale limite esprimendo transitoriamente la proteina dell'adenovirus 5 E4orf6/7, che regola il principale controllore del ciclo cellulare, E2F, insieme alla nucleasi. Mediante un'analisi dell'espressione genica globale e mirata, abbiamo dimostrato come E4orf6/7 spinga le cellule in fase S/G2 con concomitante sovra-regolazione di tutti i principali componenti del macchinario HDR, aumentando così l'efficienza dell'inserimento del transgene in cellule precedentemente quiescenti. Nel contesto dello xenotrapianto, l'espressione combinata di E4orf6/7 e l'inibizione di p53 hanno migliorato l'efficienza del HDR (>50%) all'interno dell'innesto umano totale, superando i livelli riportati fino ad ora in letteratura. Tale risultato è stato riprodotto in diversi donatori da diverse fonti di HSPC e sono stati modificati più loci genomici, dimostrando la maggior versatilità di questa piattaforma se paragonata ad altre strategie di editing. In parallelo, abbiamo ideato una nuova tecnologia (BAR-seq) che consente il monitoraggio clonale di singole HSC modificate con HDR. Questo approccio prevede l’introduzione di un codice a barre ereditabile univoco (BAR) nel templato AAV6 necessario al HDR. Il sequenziamento ad alta copertura di tali sequenze negli xenotrapianti ha mostrato come l’editing genetico risulti in un attecchimento di pochi cloni dominanti. Mentre l'inibizione transitoria di p53 durante l’editing ha consentito un aumento sostanziale della composizione clonale dell'innesto senza alterare la capacità ripopolante delle HSC. Inoltre, questi dati suggeriscono come la risposta mediata da p53 sia responsabile di un'ematopoiesi oligoclonale. È importante sottolineare che il BAR-seq ha fornito la prima prova diretta che le HSC umane modificate con HDR mantengono un potenziale multilineage e subiscono più cicli di divisioni simmetriche e asimmetriche nei trapianti primari e secondari. In conclusione, auspichiamo che i miglioramenti messi a punto nel nostro protocollo di editing possano ampliare le possibili applicazioni cliniche dell’editing genetico.The scope of genome engineering in hematopoietic stem/progenitor cells (HSPCs) has broadened from random to precise genome insertions for treating genetic diseases of the blood lineages. Targeted editing of inherited mutant genes allows in situ correction and functional reconstitution with preserved expression control. We recently showed that both the induced double-strand DNA breaks and the AAV6 genome trigger a p53-dependent DNA damage response in HSPC delaying proliferation and decreasing hematopoietic reconstitution after xenotransplantation. Suppression of this response by transient expression of a dominant negative p53 released cell-cycle block and rescued hematopoietic reconstitution. Yet, the underlying biology remained unknown as well as the impact of gene editing on clonal dynamics of HDR-edited HSPC upon transplantation. Moreover, it has long been contended that the quiescence of primitive HSC constrains HDR-mediated gene editing, thus limiting its perspective clinical applications in several diseases. Here, we first overcame such constraints by transiently expressing the adenovirus 5 protein E4orf6/7, which operates the major cell cycle controller E2F, together with the nuclease. By global and targeted gene expression analysis we showed engagement of targeted cells in S/G2 phases with concomitant upregulation of all major components of the HDR machinery, thus increasing the efficiency of targeted transgene insertion. Combined E4orf6/7 expression and p53 inhibition enhanced >50% HDR efficiency within human graft surpassing the levels reported until now in the literature. Such outcome was reproducible across several HSPC donors and sources, genomic loci and conceivably portable to most types of editing platforms. In parallel, we devised a novel technology (BAR-seq) which enables clonal tracking of individual HDR-edited HSC by introducing a unique heritable barcode in the AAV6 template. Deep sequencing of integrated BARs in human hematochimeric mice showed that only few (5-10) dominant clones of edited HSC robustly contributed to the hematopoietic graft long-term after transplant. Transient p53 inhibition during editing enabled substantial increase in polyclonal graft composition without altering individual HSC output, thus explaining the improved engraftment and highlighting the p53-mediated response as culprit of an otherwise oligoclonal hematopoiesis. Importantly, BAR-seq provided the first direct evidence that human HDR-edited HSC maintain multilineage potential and undergo multiple rounds of symmetric and asymmetric divisions in primary and secondary xenogeneic hosts. Altogether, we expect that the substantial gains obtained in HDR efficiency and polyclonal repopulation by our improved editing protocol should broaden applicability of HSC gene editing and pave its way to clinical translation.
3
Wilson, Colleen. « Nurses with human immunodeficiency virus or acquired immunodeficiency syndrome ». Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=23974.
Texte intégralRésumé :
This thesis will explore the various legal, administrative and ethical issues arising out of the situation in which nurse is HIV-positive or has AIDS. In contrast to the situation of patients suffering from AIDS or HIV, there has been little in the literature, whether legal or medical, on nurses who are infected. The rights and duties of these nurses, testing of nurses for the presence of HIV infection or AIDS and the issue of discrimination are among the matters discussed with reference to relevant legislation and ethical principles.
4
Chackerian, Bryce Charles. « Selection of simian immunodeficiency virus variants during progression to immunodeficiency / ». Thesis, Connect to this title online ; UW restricted, 1996. http://hdl.handle.net/1773/11492.
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Loo, Ryan K. « Sampling Considerations in Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome Needs Assessments ». DigitalCommons@USU, 2003. https://digitalcommons.usu.edu/etd/6179.
Texte intégralRésumé :
The human immunodeficiency virus (HIV) reduces the number of healthy immune cells in the human body. When the immune cells drop below a certain level, the person is diagnosed as having acquired immunodeficiency syndrome (AIDS), which increases the likelihood of opportunistic infections. As a result, people living with HIV I AIDS (PL WH/ A) have an elevated need for medical and support services. HIV I AIDS needs assessments identify unmet needs, and the results are used in the allocation of resources. Failure to accurately identify needs due to nonrepresentative samples may result in PL WH/ A failing to receive needed services. Random sampling is rarely used, but convenience sampling may provide representative samples if the principles of generalization are followed. The purpose of this study was to assess the degree to which lack of representation is occurring, to assess the impact of lack of representation, and to explore ways to improve the representative qualities of a sample.
6
Berglöf, Anna. « Models for infections in immunodeficiency / ». Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-333-3/.
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7
White, Stephen Mark. « Assessing the impact of the Human Immunodeficiency Virus / Acquired Immunodeficiency Syndrome on Volkswagen of South Africa ». Thesis, Port Elizabeth Technikon, 2001. http://hdl.handle.net/10948/40.
Texte intégralRésumé :
This treatise takes the form of an impact study. It is based on a three-month period of research involving literature review, interviews with VWSA officers and a survey of 111 of the 5500 workers who comprised the workforce of the VWSA plant in Uitenhage at that time. The author has attempted to portray the general views of experts in the field of HIV/AIDS corporate impact and impact management. In addition he has attempted to assay the current and forecast policies and practices in respect of the management of the epidemic by VWSA. The workers in the plant were consulted by survey and a variety of insights into the level of understanding of the epidemic, tolerance levels, expectations and so on were made. The quantification of these insights must be viewed with caution since the survey sample of 111 was relatively low for a workforce of circa 5500. Calculations in respect of representativity are included to facilitate calculated caution. It has been shown that the HIV/AIDS epidemic has a considerable current impact on the company and that this impact can be expected to grow considerably in the future. It has been suggested that an active intervention program would be well timed if implemented immediately
8
Wong, Gabriel K. « Haematopoietic clonality in common variable immunodeficiency ». Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6935/.
Texte intégralRésumé :
The aetiology of Common Variable Immunodeficiency (CVID) has fascinated immunologists since Dr. Janeway reported the first case in 1953. While the advances in molecular biology have enlightened us on the aetiology in some patients, the majority is not caused by inherited genetic disorders. A convincing mechanism accounting for the intrinsic variable and partial nature of the condition has yet been proposed. CVID separates itself from other primary antibody deficiencies by the procurement of an abnormal T-cell compartment. Data from this study support that both T-cells and B-cells are subjected to similar deficiency. Investigation of the T-cell receptor repertoire by next-generation sequencing and multi-parametric flow cytometry suggests a severe reduction in naïve T-cell output from the thymus. Similarly, the study of long-lived plasma cell generation and survival highlighted the greatest functional deficits in the naïve B-cell pool, altogether supporting an acquired arrest in lymphogenesis. Using DNA methylation as a surrogate marker for pre-VDJ clonality, this study further shows that some CVID patients exhibited clonal haematopoiesis, adjoining CVID to other clonal haematopoiesis related acquired haematological disorders. Further work is being focused on using high resolution techniques to confirm this association and mechanistically define the development of antibody deficiency in adulthood.
9
Brettle, Raymond Patrick. « Human immunodeficiency virus : the Edinburgh epidemic ». Thesis, University of Edinburgh, 1995. http://hdl.handle.net/1842/20883.
Texte intégralRésumé :
For a variety of socio-economic reasons an epidemic of injection drug use (IDU) involving heroin occurred during the early 1980's in Edinburgh: one third were female, most were young, unemployed and living on large council estates. At the peak of this IDU epidemic, HIV arrived and rapidly spread through this community. By July 1989 over 1000 individuals or 0.1% of the population of Lothian (750,000) had been recognised to have been infected with HIV, the majority via IDU. This is of the same order as the worst affected region in England (North West Thames). The majority of these individuals however live in the City of Edinburgh with a population of only around 300,000 (1981 census). Consequently a realistic prevalence for this population is actually 0.3% or 3 times the worst affected English region. Thus this new area of medicine has considerable relevance for future medicine in Edinburgh and Scotland. The thesis describes the disease, the epidemiology of Injection Drug Use and IDU related HIV and the early epidemic in Edinburgh. It also describes the clinical services that were developed at the City Hospital in Edinburgh and the problems that this new service encountered. The provision of health care for this difficult patient population facilitated a variety of research projects. The thesis describes some of the results of these projects particularly those concerned with natural history, clinical presentation and use of antiretroviral therapy in IDU related HIV. Lastly the factors found to affect the transmission of HIV to the heterosexual partners of the patients are presented together with their relevance for other populations.
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Mullighan, Charles Grenfell. « The immunogenetics of common variable immunodeficiency / ». Title page, table of contents and summary only, 1997. http://web4.library.adelaide.edu.au/theses/09MD/09mdm959.pdf.
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Currie, Peter Fox. « The cardiovascular manifestations of human immunodeficiency virus infection and the acquired immunodeficiency syndrome : prevalence, prognosis and pathogenesis ». Thesis, University of Aberdeen, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287717.
Texte intégralRésumé :
The main aim of the work presented in this thesis was to delineate the natural history and pathogenesis of HIV related heart muscle disease. Additional studies examined the influence of HIV infection on the risk and course of infective endocarditis. Two hundred and ninety-six HIV positive adults were examined by echocardiography in a four year prospective study. Abnormal cardiac function was identified in 14.8%. Dilated cardiomyopathy was present in 4.4% borderline left ventricular dysfunction in 6.4% and isolated right ventricular dysfunction in 4%. Dilated cardiomyopathy was strongly associated with reduced survival compared to those with normal hearts (median survival from diagnosis 101 days, compared to 472 days for those with structurally normal hearts). A newly developed ELISA for anti α-myosin autoantibodies revealed abnormal results in 43% of patients with HIV heart muscle disease, 19% of HIV positive patients with normal hearts and 3% of HIV negative controls. Cardiac specific autoantibodies were also more common in HIV positive patients. Autoimmunity may therefore be important in the pathogenesis of HIV related heart muscle disease. There were no significant socio-economic differences between the HIV positive patients with and without heart disease or the lifestyle matched HIV negative controls studied but mean serum selenium was 33% lower in the HIV positive individuals. Similar differences in toenail (15% lower) and myocardial (17% lower) levels and glutathione peroxidase (15% lower) were also found, but there were no specific differences between patients with and without cardiac abnormalities. Mean α- and γ- tocopherol and α- and β- carotene levels were significantly reduced in our HIV positive patient group, compared to the local HIV negative population, but similar differences existed in a socio-economically matched group of HIV negative drug users. Intravenous drug use was the most important risk factor for the development of the condition.
12
Wagner, Sarah Annette. « Perinatal human immunodeficiency screening in Washington State ». Online access for everyone, 2006. http://www.dissertations.wsu.edu/Thesis/Spring2006/s%5Fwagner%5F041406.pdf.
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Cochrane, Alexandra. « Human immunodeficiency virus infection of CD8 lymphocytes ». Thesis, University of Edinburgh, 2006. http://hdl.handle.net/1842/24468.
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To confirm that CD8 lymphocytes are infected with HIV in vivo, and to investigate the mechanism of infection, HIV long terminal repeat (LTR) DNA was quantified in CD8 lymphocyte subsets of known purity, isolated from the blood of 20 subjects with HIV infection. HIV LTR was demonstrated in CD8 lymphocytes of 18/20 subjects, and in the subjects with chronic infection the frequency of infection increased with disease progression. HIV infection of CD8brightCD4dim lymphocytes was significantly more frequent (median 1197 HIV LTR copies / million cells) than that of CD8+CD4- lymphocytes (undetectable in 7/9 subjects, p<0.01) suggesting infection on activation rather than during intrathymic development. The level of infection in the CD8brightCD4dim lymphocytes approached that in CD4 lymphocytes from the same subjects (median 3660 HIV LTR copies / million cells) and therefore could not be explained by CD4 lymphocyte contamination. Given the high level of infection of CD8brightCD4dim lymphocytes their prevalence and phenotype was assessed in 8 healthy and 16 HIV infected subjects. The proportion of CD8 lymphocytes with a CD8brightCD4dim phenotype ranged from 0.3 to 3.4% with no significant difference between HIV infected and healthy subjects. The majority displayed a CD45RA-ve CD27+ve (memory) phenotype, but in contrast to the populations generated in vitro, the circulating population was not uniformly activated but rather comprised both activated and quiescent cells. Thus HIV infected CD8 lymphocytes commonly circulate in HIV infected subjects, and are likely to be infected on activation rather than during intrathymic development. Given that a proportion of the circulating CD8brightCD4dim lymphocytes have a quiescent phenotype, they may act as a long lived reservoir with implications for viral eradication.
14
Goodship, Judith Anne. « Molecular genetics of X-linked immunodeficiency disorders ». Thesis, University of Edinburgh, 1990. http://hdl.handle.net/1842/26547.
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Eight disorders of the immune system have been described which are inherited as X-linked recessive conditions. The aim of this study has been to improve predictive testing in X-linked agammaglobulinaemia (XLA) and X-linked severe combined immunodeficiency (XSCID) and to investigate the underlying defect in XSCID. Precise genetic localisation is essential for accurate predictive testing and in order to develop strategies to clone the genes. Before disease localisation can be improved it is necessary to clarify the order of a number of probes within the region of interest. Fourteen genetic markers assigned to the X chromosome between the pericentromeric region and Xq22 were ordered by family studies and deletion mapping. Pulsed field gel electrophoresis was used to make a physical map of the markers linked to XLA. Knowledge of the order of these anonymous DNA probes led to finding additional linked probes for both diseases. This makes predictive testing possible in more families. There are X-linked and autosomal recessive forms of severe combined immunodeficiency. This has caused difficulties in counselling couples who have an affected male child and where there is no previous family history of the disease. In this study it has been shown that female carriers of the X-linked disorder have non-random use of the X chromosome in T lymphocytes. This provides a means of distinguishing between the autosomal and X-linked forms which enables more accurate genetic counselling. XSCID has been mapped to Xq11-q13 using DNA markers which detect polymorphic variation (de Saint Basile et al, 1987). No recombinations have been observed between the disease locus and the anonymous DNA probe cpX289. In this study the PGK1 locus was also shown to be closely linked to the disease. Using both of these linked markers predictive tests can be offered to 65% of families. The probe pSPT/PGK which detects a polymorphism at the PGK1 locus can also be used to investigate X chromosome usage. In females who are heterozygous for the polymorphism detected by this probe, carrier detection and assignment of phase can be carried out in the same procedure. This is a unique situation and is particularly useful when the proband could carry a new mutation or when there are no males available who can be used to assign linkage phase. It has been thought that XSCID results from a defect in a T lymphocyte specific gene because the phenotype is predominantly a lack of T lymphocytes and because host B lymphocytes produce functional antibody following transplantation and engraftment of T lymphocytes. Finding a non-random pattern of X chromosome usage in a mature cell population implies that the defective gene is expressed in that cell type and this technique was used to investigate gene expression. Non-random X chromosome usage was found in T lymphocytes, B lymphocytes, monocytes and granulocytes. The pattern of expression suggests that the underlying defect in XSCID is in a general metabolic pathway rather than a pathway specific to lymphocytes.
15
Sharpe, Sally Anne. « T cell responses to simian immunodeficiency virus ». Thesis, Open University, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361381.
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Caney, Sarah Madeline Amanda. « Mucosal immunopathogenesis of feline immunodeficiency virus infection ». Thesis, University of Bristol, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341499.
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Camerini, Valentina. « Translational control of feline immunodeficiency virus (FIV) ». Lyon, École normale supérieure (sciences), 2006. http://www.theses.fr/2006ENSL0387.
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Buck, Wayne R. « Neuropathogenic mechanisms of feline immunodeficiency virus infection ». Columbus, Ohio : Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1078414064.
Texte intégralRésumé :
Thesis (Ph. D.)--Ohio State University, 2004.Title from first page of PDF file. Document formatted into pages; contains xiv, 144 p.; also includes graphics (some col.). Includes abstract and vita. Co-advisors: Lawrence E. Mathes and Maria H. Neff, Dept. of Veterinary Biosciences. Includes bibliographical references (p. 122-144).
19
Stubbs, Samuel Christopher. « The virome in primary and secondary immunodeficiency ». Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/277043.
Texte intégralRésumé :
The afflictions suffered by immunocompromised individuals have historically been attributed to overt infections caused by bacterial and fungal pathogens. For this reason, treatment methods have focused on resolving these infections, with great success in terms of reducing short-term morbidity and mortality rates. This initial success only served to reinforce the dogmatic opinion that to ‘cure’ immunodeficiency, one needs only to resolve and prevent recurrence of bacterial and fungal infections. However, reports of long-term health problems in immunocompromised cohorts suggest that treatment of bacterial and fungal infections alone does not resolve all aspects of the disease, and that viruses may play a greater role than previously expected. This thesis investigates whether viral infections do indeed have a significant impact in the immunocompromised patient. The overall prevalence of blood-borne viral infections in immunocompromised cohorts was determined through the combined use of unbiased, metagenomic sequencing and qPCR. The viral species detected were compared with patient records in order to determine whether there were any correlations between viral presence and patient outcome following treatment. Furthermore, by investigating a cross-section of cohorts with both inherited and acquired immunodeficiences, commonalities and differences could be found in terms of the types of viruses that infect these cohorts and their abundance in patients with different types of immunodeficiency. The findings of this work suggest that a large number of clinically undiagnosed viruses infect immunocompromised patients, however the prevalence of these viruses varies according to the form of immunodeficiency and, to a lesser extent, according to differences between individuals in the same cohort. Importantly, some of the more common viruses detected appear to be correlated with poor patient outcomes such as graft rejection and future infectious complications. Overall, these results suggest that viral infections do indeed play a larger role in the health of immunocompromised patients than has previously been thought although whether this is due to a direct cause or as a consequence is yet to be determined.
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CHIRIACO, MARIA. « Molecular and biological aspects of primary immunodeficiency ». Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2009. http://hdl.handle.net/2108/1126.
Texte intégralRésumé :
Le immunodeficienze primitive (PID) costituiscono un gruppo eterogeneo di disordini genetici causati da alterazioni delle varie componenti della risposta immune innata ed adattiva. Più di 120 geni sono stati identificati come responsabili delle oltre 150 differenti forme PID.
L’eterogeneità genetica e del fenotipo clinico, quest’ultimo caratterizzato da un’alta suscettibilità alle infezioni spesso associata a manifestazioni allergiche, linfo-proliferative ed autoimmuni, rende le immunodeficienze un ottimo modello per lo studio dei meccanismi che regolano lo sviluppo e la funzione del sistema immunitario. Questo lavoro ha lo scopo di suggerire un approccio allo studio delle PID attraverso un’attenta valutazione clinica, genetica e molecolare (studio1 e studio2) e di proporre la terapia genica come cura risolutiva nel caso di immunodeficienze dovute ad un definito difetto genico (studio 3).
Studio1: Lo studio di un paziente con disgammaglobulinemia ed una graduale diminuzione dei linfociti B nel sangue periferico, ha rivelato la presenza di una nuova mutazione nel gene Btk che non compromette l’espressione della proteina. Sebbene la storia clinica e di laboratorio, non è totalmente inconsistente con una variante atipica di XLA, non siamo ancora in grado di stabilire se il quadro clinico è dipendente da questa nuova mutazione o dalla combinazione di più mutazioni che interessano geni diversi.
Studio2: Descriviamo per la prima volta un caso di paziente femmina con immunodeficienza combinata caratterizzata dalla completa assenza delle cellule B, NK e dei loro progenitori ematopoietici. Sorprendentemente la paziente non ha monociti (CD14+) e cellule dendritiche. L’analisi di sequenza dei geni Flt3R e Flt3L e dei geni che principalmente regolano la loro espressione (Ikaros e PU.1), non ha evidenziato alcuna mutazione. I livelli di Flt3R mRNA e Flt3R mRNA nel sangue periferico risultano significativamente più alti (10- e 30- volte aumentati rispettivamente) rispetto al controllo sano, supportando così la nostra ipotesi di uno sbilanciamento dell’espressione dell’mRNA dell’Flt3 ligand. Questi risultati considerati alla luce di uno stroma funzionale nella nostra paziente, potrebbero suggerire il trapianto come strategia terapeutica futura.
Studio3: La terapia genica potrebbe rappresentare la cura definitiva di pazienti per i quali non è possibile fare il trapianto di midollo. Sin dal 997, diversi trial clinici per la terapia genica della XCGD sono stati proposti, ma non sono mai risultati efficaci per una cura a lungo termine. In questo studio noi sviluppiamo una nuova strategia per la terapia genica in pazienti XCGD, basata sui vettori lentivirali e la nuova tecnologia dei microRNA per un controllo del transgene ad un livello post-trascrizionale.Background: Primary immunodeficiency diseases (PIDs) comprise a genetically heterogeneous group of disorders which affect distinct components of the innate and adaptive immune system. Over 120 distinct genes have been identified, whose abnormalities account for more than 150 different forms of PID. Clinical presentation is highly variable; actually ranging from various patterns of microbial susceptibility to allergy, lymphoproliferation or autoimmune manifestations. The study of patients affected by immunodeficiencies allows to identify new genes involved in the immune response indeed PIDs represent an optimal model to investigate development, function and regulation mechanisms of immune system. Aim of the study: To define a rational approach to recognize immune deficiencies, with specific emphasis on developing clinical evaluations, understanding the genetic and cellular basis of the disease (Study1 and Study 2), and propose a gene therapy approach as a definitive cure of immunodeficiency due to a defined genic defect (Study3). study1: We report a patient with dysgammaglobulinemia, and gradual decrease of peripheral B lymphocytes. A new Btk mutation was identified in this patient and protein expression was determined. Although clinical and laboratory history is not totally inconsistent with an atypical variant of XLA, it is unclear if all the clinical presentation/picture is influenced by the new mutation. Study2: We report for the first time a case of a female patient with combined immunodeficiency characterised by a complete absence of B cells and NK cells, and their progenitors. Surprisingly, she had an absence of monocytes (CD14+) and DC cells. Direct sequencing of genomic and cDNA of Flt3L, Flt3R, and of major genes (Ikaros and of PU.1) regulating the FLT3-FLT3L expression did not show the presence of any mutations. Levels of Flt3R and Flt3L mRNA in peripheral blood resulted significantly higher (10- and 30- fold increase respectively) with respect to healthy control donor, supporting the hypothesis of an inherited imbalance in the expression of Flt3 ligand mRNA. This finding, in addition to a normal stromal function highlights the possibility of a more specific therapeutic strategy in this child, such as haematopoietic stem cells transplantation. Study3: Gene therapy could represent a definitive cure for patients for whom conventional HSCT is not available. Several clinical trials on XCGD-gene therapy have been conducted since 1997, but they resulted in low and short-term engraftment of CGD-corrected cells. In this study we develop a new strategy for XCGD gene therapy with stem cells, including Lentiviral Vector (LVV) design and microRNA technology, for a safe and effective treatment of X-CGD.
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Hughes, Richard J. « Production of cowpea mosaic-human immunodeficiency virus chimeras in an attempt to generate a vaccine to acquired immunodeficiency syndrome ». Thesis, University of Warwick, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.429749.
Texte intégral
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Langeni, Delile Gertrude. « Self-Disclosure of Human Immunodeficiency Virus Status in Personal Relationships : Perceptions of South Africans Living with Human Immunodeficiency Virus ». ScholarWorks, 2018. https://scholarworks.waldenu.edu/dissertations/4798.
Texte intégralRésumé :
Despite enormous research on the experience of living with HIV, many questions remain regarding self-disclosure of HIV status to sexual partners by people living with HIV (PLWHIV), which is essential to reducing further infection. In this study, a phenomenological approach captured the experience of self-disclosure among South Africans living with HIV in Louwsburg, South Africa. The health belief model served as a theoretical framework, and in-depth interviews were conducted with 12 PLWHIV (8 women, 4 men) who self-disclosed their HIV status to their sexual partners. Their experiences were explored, discovering their illness, motives for self-disclosure, feelings regarding disclosing, responses of their sexual partners, their emotional reaction, and about their medical care. The themes rose from interviews showed that (a) many PLWHIV are reluctant to self-disclose until they actively experienced health issues; (b) motives for disclosure include the wish to ensure fairness; support and to empower other PLWHIV to prevent further infection; (c) feelings of disclosure are primarily relief and liberation, even though risks remain, especially for families separated by labor migration laws; (d) the response of sexual partners to disclosure varies widely; some are motivated to get tested and use condoms, decline and respond only with anger, blame, even abandonment; and (e) after accessing medical care, most PLWHIV reported support and appearing less sick, which reduces social stigma. The women were more open, forthcoming, and transparent about disclosing than men participants. Findings will assist with the creation of future health education programs aimed at creating safe environments to disclose HIV status, which may reduce community risk of contracting the virus.
23
Graf, Daniel. « Cloning and characterziation of TRAP (CD40 Ligand) and its role in the primary immunodeficiency 'X-linked immunodeficiency with hyper-IgM' / ». [S.l.] : [s.n.], 1994. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=10753.
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Shi, Ruili. « Biological studies on inhibitors of human immunodeficiency virus ». Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0024/NQ37913.pdf.
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Pike-Overzet, Karin. « Gene therapy for RAG-deficinet severe combined immunodeficiency ». [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2007. http://hdl.handle.net/1765/10651.
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McKiel, Vanessa. « Cytokine-induced alterations in human immunodeficiency virus multiplication ». Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=55512.
Texte intégralRésumé :
The ability of the human immunodeficiency virus (HIV) to replicate in T-cells and macrophages has been shown to be influenced by immunomodulatory cytokines; furthermore, HIV infection of these cells can alter the kinetics of cytokine transcription. We found that chronic HIV IIIB infection of myelomonoblastic PLB 985 cells resulted in an altered pattern of type 1 interferon (IFN) transcription. Paradoxically, despite the antiviral effects of IFN, HIV-induced dysregulation of IFN transcription may actually lead to the establishment of a cellular environment that supports a chronic infection.Since HIV replication is dependent on cellular activation, immunosuppressive cytokines which deactivate T-cells and macrophages may be important modulators of an antiviral effect. We previously demonstrated the anti-HIV effects of IFN$ alpha$2, alone and in a cooperative combination with 3$ sp prime$-azido-2$ sp prime$3$ sp prime$-dideoxythymidine (AZT), in limiting the expression of HIV IIIB in promonocytic U937 cells. We further tested the anti-HIV potential of the immunosuppressive cytokines transforming growth factor beta (TGF-$ beta$1) and interleukin-10 (IL-10), alone and in combination with AZT. TGF-$ beta$1 as a single agent had no effect on the multiplication of HIV IIIB in de novo infected PLB 985 cells; however, co-treatment with TGF-$ beta$1 and AZT synergistically slowed virus multiplication within the first week following infection. The synergistic actions of TGF-$ beta$1 and AZT were also observed in PLB 985 cells infected with an AZT-resistant strain of HIV-1. In contrast, IL-10 seemed to enhance HIV IIIB multiplication in PLB 985 cells. These antiviral treatments had no inhibitory effect on HIV IIIB multiplication in the T-cell line Jurkat. Elucidation of the role of cytokines in controlling the degree of HIV multiplication may have an impact on both clinical treatments and understanding the progression to AIDS.
27
Williams, Paul Eirian. « Aspects of antibody replacement therapy in human immunodeficiency ». Thesis, University of Oxford, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235954.
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Evans, Paul Michael. « An investigation of cellular radiosensitivity associated with immunodeficiency ». Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1444432/.
Texte intégralRésumé :
DNA Double Strand Breaks (DSBs) are induced by ionising radiation, but also arise during normal physiological processes such as V(D)J recombination during lymphocyte development. The induction of DSBs leads to the activation of proteins involved in DNA repair, but also initiates p53 dependent pathways that can result in cell cycle arrest and/or apoptosis. Defects in this damage response network may therefore result in immunodeficiency and cellular radiosensitivity. Skin biopsies obtained from undefined immunodeficient patients were used to generate primary fibroblast lines, and a group of these demonstrated cellular radiosensitivity using fibroblast survival assays. Whilst radiation-induced lymphocyte apoptosis was found to be an unreliable measure of intrinsic radiosensitivity, the examination of fibroblast division early after irradiation determined that radiosensitive fibroblasts undergo distinct cell fates after irradiation. Further characterisation revealed that all the identified radiosensitive lines were able to initiate p53-dependent gene transcription after irradiation. Analysis suggested that one undefined line (F96) might harbour a defect in DSB repair. Sequence examination of F96 candidate genes confirmed the presence of 2 novel mutations in the Artemis DNA repair gene that were expressed from separate alleles. Cloning of the Artemis gene also allowed the discovery of a new alternative exon and many novel splice variants. Concurrently, the F96 line was found to induce abnormally high levels of p53 activation after irradiation, which was associated with a more widespread induction of p53 target genes. This indicated that after DNA damage, defects in DSB repair might combine with other genetic factors that impair cellular survival to confer a radiosensitive immunodeficient phenotype.
29
Fox-Clipsham, Laura Yana. « Foal immunodeficiency syndrome : identification of the causal mutation ». Thesis, University of Liverpool, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.569771.
Texte intégralRésumé :
Foal Immunodeficiency Syndrome (FIS), is a disease that affects both Fell and Dales Ponies. FIS results in a profound anaemia and a severe deficiency in the number of circulating Bvlymphocytes. Consequently, FIS-affected foals begin to lose condition and suffer from multiple opportunistic infections; FIS is eventually fatal. Pedigree analysis, incorporating the knowledge of FIS-affected individuals, suggested that FIS is a genetic disorder, with an autosomal recessive mode of inheritance. Further, analysis of the Fell and Dales Pony stud book revealed a common founder stallion, in the maternal and paternal lineage of all Fell and Dales FIS-affected individuals. Based on this, the primary aim of this investigation was to characterise the genetic lesion responsible for FIS, and subsequently develop a diagnostic test which could be used to identify asymptomatic carriers. Two approaches were taken in this study to definitively map the FIS locus; a micro satellite whole-genome scan, and a genome-wide association study. Linkage analysis and homozygosity mapping of the micro satellite marker data revealed a single locus which showed significant linkage to FIS. This was then further supported with the genome-wide association study, using the EquineSNP50 Beadchip, which identified the same locus with a significant disease association. After additional fine-mapping of the associated region, four plausible candidate genes were identified and subsequently investigated, although none revealed the causative mutation. Therefore, the entire FIS critical interval was sequenced using next-generation re-sequencing. This led to the identification of a non-synonymous single nucleotide polymorphism, in the single ex on of the sodium/myo-inositol cotransporter gene (SLC5A 3) , which is highly associated with the FIS phenotype. This gene plays a crucial role in the osmoregulation of tissues, a process which has been shown to be extremely important in the development of lymphoid tissues, lymphocytes, peripheral nerves and during early embryonic development. Further functional studies are now required to assess the functional consequences of this mutation. The identification of this mutation has led to the development of a diagnostic test, which is not only used to identify asymptomatic carriers of FIS, but also to definitively diagnose foals which are suspected FIS-affected. Additionally, this test has been used to perform a population screen, to assess the prevalence of the FIS mutation and investigate possible transfer into other equine breeds. This revealed that carrier prevalence is approximately 40-50% in the Fell Pony and 10-20% in the Dales Pony. Further, this confirmed that the FIS mutation had transferred into the Coloured pony population. Global transcriptional changes in FIS-affected foals were evaluated as part of a pilot study. This revealed significant disruption of multiple pathways, including those responsible for the haematological system and its development, tissue development and cell growth. Due to the severe clinical presentation of the FIS-affected foals used in this study, this data provides limited information on primary consequences of the causal variant. Rather it provides a snapshot of the transcriptional changes associated with the downstream effects of the FIS-causal variant and the multiple pathological effects associated with this.
30
唐娴 et Xian Tang. « Mechanisms of immune protection against simian immunodeficiency virus ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hdl.handle.net/10722/193064.
Texte intégralRésumé :
The lack of an effective HIV vaccine calls for efforts to investigate the
mechanism of protective immunity against AIDS viruses. It has been previously
demonstrated that the live replication-competent modified vaccinia virus Tiantan
(MVTT) is superior to non-replication vaccinia MVA in inducing high levels of
neutralizing antibodies against SARS-CoV infection via mucosal vaccination.
Therefore, the hypothesis was that MVTT could be a better HIV vaccine vector
given its highly attenuated phenotypes such as no neurovirulence and safe in severe
combined immunodeficiency disease (SCID) mice. Here, a recombinant MVTT
expressing SIVmac239 Gag-Pol and Env (rMVTTSIVgpe) was constructed and its
immunogenicity was assesed when administered via different routes using
homologous prime-boost strategies or in heterologous regimens boosted with a
recombinant adenovirus-based vaccine inserted matched SIVmac239 genes
(rAd5SIVgpe). Results show that the heterologous prime-boost immunization with
rMVTTSIVgpe and rAd5SIVgpe induces significantly greater humoral and T cell
responses specific to SIV Gag, Pol and Env than homologous inoculations in mice
with remarkable improvements in quality and quantity.
The further study comparing different combinations of rMVTTSIVgpe and
rAd5SIVgpe demonstrates that the rMVTTSIVgpe prime-rAd5SIVgpe boost regimens
elicit systemic CD8+ T cell responses with augmented magnitude and
polyfunctionality, as compared with rAd5SIVgpe-rMVTTSIVgpe and
rAd5SIVgpe-rAd5SIVgpe regimens. Priming with rMVTTSIVgpe also increases
frequencies of gut-homing Gag-specific CD8+ T cells (CCR9+47+ and
CCR6+47+) and levels of CD8+ T cell ELISPOT responses against Gag, Pol and
Env in mesenteric lymph nodes (MLNs) post-boost. The mucosal route of
immunization is essential for rMVTTSIVgpe to induce rectal IgG with detectable
neutralizing activity against SIVmac1A11. Furthermore, the regimen involving
mucosal prime with rMVTTSIVgpe followed by systemic boost with rAd5SIVgpe
proves to be efficient in protecting monkeys from mucosal challenge of a high dose
of SIVmac239, a CCR5-tropic strain with high pathogenicity and
neutralization-resistance. SIV-specific T cell ELISPOT responses specific to Gag
and Pol but not Env and the frequency of Gag-specific IFN-+TNF-+CD8+
effector memory T cells (TEM) are likely associated with virological control after
challenge. Mucosal immunity induced by this vaccination strategy also has
important implications to the effectiveness of protection against disease
progression.
A hypothesis was generated that removal of non-protective but immune
dominant determinant of SIVmac239 Env may drive antibody responses to
protective domains. It was found that the neutralization-resistance of SIVmac239
could be partially explained by its high immunogenicity in eliciting CD4-induced
neutralizing antibodies, which are unable to protect the CCR5-binding site due to
the conformational masking and steric restriction. It was discovered that the
immunodominance of CD4-induced neutralizing antibodies on SIV envelope is
determined by a single highly conserved N-linked glycosylation site (N277) in the
C2 domain. Substitution of this N-linked site abolishes viral entry and the
immunogenicity of the CD4i domain while promotes V2-specific antibody
responses, which have recently been identified as an important immunological
correlate to HIV-1/SIV protection. Our findings demonstrate the concept that B cell
immunodominance is relative and eliminating the dominant antigenic region can
result in redirection of B cell recognition, which have critical implications for
immunogen design and the development of protective antibody-based HIV vaccine.published_or_final_version
Microbiology
Doctoral
Doctor of Philosophy
31
Mooster, Jana. « Mechanisms of Immunodeficiency Due To NFkappaB Signaling Defects ». Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10389.
Texte intégralRésumé :
Ectodermal dysplasia with immunodeficiency (ED-ID) is a rare primary immunodeficiency syndrome characterized by defects in ectodermal tissues (skin, hair and sweat glands), recurrent infections, impaired response to Toll-like receptor ligands, hypogammaglobulinemia and deficient antibody production. It is caused by defective \(NF\kappa B\) signaling. The most common form of ED-ID is X-linked. It is caused by hypomorphic mutations in the \(NF\kappa B\) essential modifier gene NEMO, which is an important regulatory component in the \(NF\kappa B\) signaling pathway. We report the first case of ED-ID caused by insufficient expression of a NEMO protein of normal sequence, due to a mutation in the 5’ untranslated region of the NEMO gene. Autosomal dominant ED-ID, a rare form of ED-ID, has been reported to be caused by a heterozygous S32I mutation in the \(I \kappa B \alpha\). This mutation prevents IκBα phosphorylation and inhibits its degradation. The mutant sequesters \(NF\kappa B\) in the cytoplasm and acts as a dominant negative. We report the first ED-ID patient with a heterozygous mutation (W11X) that causes N-terminal truncation of \(I \kappa B \alpha\) and results in functional haploinsufficiency. We have constructed a knock-in mouse model of ED-ID caused by a heterozygous S32I mutation in \(I \kappa B \alpha\). The mutant mice had ED, increased mortality, complete lack of lymph nodes and Peyer’s patches, and disorganized spleens that lacked follicles, marginal zone B cells and follicular dendritic cells. T cell proliferation and cytokine production was normal in vitro, but in vivo contact hypersensitivity was severely impaired, B cell function in vitro and specific antibody response to antigens were severely reduced. All immune defects, except those that affected B cell function, were absent in \(I \kappa B \alpha\) S32I mutant \(Rag2^{-/- }\) bone marrow chimeras, indicating that defects in non-lymphiod cells play a major role in the immunodeficiency of patients with ED-ID due to mutations in \(I \kappa B \alpha\). This has important clinical implications, as bone marrow transplant may not be able to correct immune function in such patients. The lessons learned in these chapters may be applicable to other mutations that impair \(NF\kappa B\) signaling and have important implications for the treatment of patients who carry these mutations.
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Haining, Hayley. « Studies of the pathogenesis of feline immunodeficiency virus ». Thesis, University of Glasgow, 2004. http://theses.gla.ac.uk/5512/.
Texte intégralRésumé :
The project had three aims: namely: - (i) to investigate the in vitro cell tropism of a range of field isolates from cats at different stages of disease and compare their phenotype with the well-characterised prototype viruses FIV-PET and FIV-GL8. (ii) to study the pathogenicity of these viruses in vivo in order to examine any correlation between virulence in vivo and tropism in vitro. (iii) to look at the role of the env gene in the pathogenicity of FIV. In vitro studies of cell tropism revealed that isolates from cats in the terminal stage of disease had a greater ability to utilise CXCR4 than isolates from cats displaying no clinical signs. In vivo, these symptomatic isolates, with greater CXCR4-tropism in vitro, displayed less virulence when compared with isolates from asymptomatic cats. Chimaeras were made by inserting the env genes of an isolate from the asymptomatic or terminal disease stages into a FIV-G8Mya backbone, allowing comparison of the cell tropism and receptor usage of these genes and the study of their phenotype with regard to virulence in vivo. The env genes from FIV-PET and the symptomatic isolate (F0827Hs) had a greater affinity to utilise CXCR4 for cell entry in vitro and this correlated with reduced virulence in vivo when compared to the asymptomatic isolate env and FIV-G8Mya. These studies highlight a trend where tropism in vitro can be correlated with virulence in vivo. Furthermore, the study indicated that viruses from asymptomatic cats (with a lesser ability to utilise CXCR4) have increased virulence. As these are the agents most likely to be transmitted in the field by the apparently healthy cat, vaccine development should focus on this population of viruses.
33
Harrison, Thomas Stephen. « Interactions between Human Immunodeficiency Virus and Cryptococcus neoformans ». Thesis, St George's, University of London, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299059.
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Walker, S. M. « Transactivation of human immunodeficiency virus by human cytomegalovirus ». Thesis, University of Cambridge, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.387104.
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Krick, Kari Elizabeth. « Exercise and Immunodeficiency Affect Immunoglobulins in Endurance Horses ». Thesis, Virginia Tech, 2002. http://hdl.handle.net/10919/43971.
Texte intégralRésumé :
Two studies were conducted on endurance horses predominantly of Arabian breeding participating in an 80 km ride dedicated to research in April 2001 (Trial 1) and April 2002 (Trial 2). Objectives were to determine effects of endurance exercise, antioxidant supplementation, and a feed rich in fiber and fat vs. a high fat sweet feed on immunoglobulin A and G concentrations as well as identify selective IgA deficiency in endurance horses of Arabian breeding. There were no effects of distance in Trial 1 on IgA (P = 0.73) or IgG (P = 0.18) concentrations. In Trial 2, IgA concentrations increased (P = 0.05) and IgG concentrations increased (P = 0.006) after the start of the race. There were no effects of antioxidant supplementation on IgA (P = 0.16), IgG (P = 0.16), and IgM (P = 0.70) concentrations. There were no diet effects on IgA (P = 0.80), IgG (P = 0.59), and IgM (P = 0.54) concentrations. There were horses in both trials that were deficient in IgA only. Concentrations of IgG and IgM were within normal ranges, and there were no differences in training, performance and transportation variables, IgG concentrations, antioxidant supplementation, and feed supplementation compared to the horses with normal IgA concentrations. The concentration of IgM was higher in IgA deficient horses in Trial 1 (P = 0.035) and Trial 2 (P = 0.017). Horses with deficient IgA tended to be associated with health problems commonly found in humans and dogs affected with selective IgA deficiency.Master of Science
36
Chua, Ser Ling. « Papular pruritic eruption of human immunodeficiency virus infection ». Thesis, University of Nottingham, 2015. http://eprints.nottingham.ac.uk/30750/.
Texte intégralRésumé :
Background Papular pruritic eruption (PPE) of human immunodeficiency virus (HIV) infection is common HIV-infected populations who live in tropical and subtropical regions. It is characterized by chronic and intensely itchy papules that are usually more highly concentrated on the extremities, adversely impacting on quality of life. Its aetiology has been postulated to be an altered and exaggerated immunological response to insect bites or stings. It has been reported to diminish in severity or resolve with antiretroviral therapy (ART). Its presence after at least six months of ART has been proposed as one of several clinical markers of failure of antiretroviral treatment. Objectives 1. To systematically summarise the evidence of interventions for PPE 2. To translate, culturally adapt, and test oral administration of a Runyankore-version of Skindex-16 for use in dermatology research in Mbarara, Uganda 3. To determine factors associated with PPE in HIV-infected Ugandan adults receiving ART for at least 15 months 4. To describe the natural history of PPE in HIV-infected Ugandan adults over two years from the time of ART initiation and explore the association between recurrent or persistent PPE and antiretroviral treatment failure Methods Systematic review of interventions for PPE Electronic searches of Medical Literature Analysis And Retrieval System Online (Medline), Excerpta Medica Database (Embase), Cumulative Index To Nursing And Allied Health Literature (CINAHL), Global Health Library, Cochrane Library, World Health Organization (WHO) International Clinical trials registry and National Library Of Medicine (NLM) gateway were carried out from January 1980 to July 2014. Studies of any design were included. The primary outcome measure for this review was resolution of skin disease. The quality of evidence was assessed using the Newcastle-Ottawa quality assessment scale and Grading Of Recommendation, Assessment, Development And Evaluation (GRADE) approach, where appropriate. Two authors carried out data extraction and quality assessment of studies independently. Runyankore-version of Skindex-16 for oral administration in Mbarara, Uganda Skindex-16 in English was translated to Runyankore, and then back-translated to English. The original and back-translated versions of Skindex-16 were compared for fidelity of translation. The Runyankore-version was administered orally to 47 dermatology patients and 47 random hospital visitors. Study participants were also asked about the characteristics of their skin condition including its duration, presence of skin colour change and ease or difficulty of concealment as well as an open question on how their skin condition has affected them. Case control study examining factors associated with PPE in the ART era This is a case–control study nested within a 515-person cohort receiving care at the HIV clinic of a teaching hospital in Mbarara, Uganda. Forty-five cases and 90 controls were enrolled. Cases had received ART for ≥15 months, fulfilled the clinical case definition of PPE and had skin biopsy findings consistent with PPE. Each case was individually matched with two controls for age, sex and ART duration. Cohort study describing the natural history of PPE over two years from ART initiation This is a cohort study of HIV-infected Uganda adults initiating ART and receiving care at the HIV clinic of a teaching hospital in Mbarara, Uganda who fulfilled the clinical case definition of PPE and had skin biopsy findings consistent with PPE. Standardised interviews, clinical photography, HIV viral load, CD4 counts and CD8+ T-cell activation markers were measured at three-month intervals for two years. Results Systematic review of interventions for PPE No randomised controlled trials were identified. Thirteen studies with a total 188 participants were included. ART was associated with resolution of PPE in a prospective observational study that had high loss to follow-up rates. Two observational studies reported positive responses of PPE to oral antihistamines (promethazine and cetirizine). Pentoxifylline was associated with diminished signs and symptoms of PPE in an uncontrolled open trial and superior to dapsone and a combination of antihistamine and topical corticosteroids in a parallel group non-randomised trial. Resolution of PPE was reported with a combination of topical corticosteroids and oral antihistamines in a case report. The efficacy of ultraviolet B (UVB) phototherapy was reported in an observational study with eight participants and three case studies with a total of five participants. Runyankore-version of Skindex-16 for oral administration in Mbarara, Uganda Oral delivery was feasible, taking ≤10 minutes per subject. High Cronbach α values (0.86, 0.88 and 0.85 for Symptoms, Emotions and Functioning subscales, respectively) demonstrated internal consistency reliability. As hypothesised, subjects with reported skin problems, dyspigmentation and difficulty in concealment had higher mean Skindex-16 scores, indicating construct validity. A large proportion (72.4%) of responses to the open-ended question were addressed in Skindex-16, indicating content validity. Case control study examining factors associated with PPE in the ART era Twenty-five of 45 cases (56%) had histological findings consistent with PPE (known as PPE cases). At skin examination and biopsy (study enrolment), a similar proportion of PPE cases and their matched controls had plasma HIV RNA <400 copies/ml (96% vs. 85%, p=0·31). The odds of having PPE increased four-fold with every log increase in viral load at ART initiation (p=0.02) but not at study enrolment. CD4 counts at ART initiation and study enrolment, and CD4 gains and CD8 T-cell activation measured 6 and 12 months after ART commencement were not associated with the presence of PPE. Study participants who reported daily insect bites had greater odds of being cases [odds ratio (OR) 8.3, p<0.001] or PPE cases (OR 8.6, p=0.01). Cohort study of natural history of PPE over 2 years from ART initiation Seventeen (15 female and 2 male) participants with a median age of 29.8 years were enrolled. Median CD4 count and HIV viral load at ART commencement was 108 cells/mm3 and 114,442 copies/ml, respectively. Resolution of PPE occurred in 13 of 17 (76%) study participants at a median time of 8.5 months after ART initiation, although PPE recurrence was observed at seven participants during the study period. Two participants had persistent PPE. Virological failure was not detected in any study participant. HIV RNA was less than 400 copies/ml at a median time of three months from ART initiation in all study participants. Conclusions 1. The evidence base of interventions for PPE is of low quality. There is some evidence of the efficacy of ART in the management of PPE. Pentoxifylline and phototherapy may have a role in its management but are unlikely to be available in resource-limited settings. Oral antihistamines and topical corticosteroids may be helpful in some individuals affected by PPE. 2. The orally administered Runyankore-version of Skindex-16 is reliable, with construct and content validity, and feasible for use in dermatology research in Mbarara, Uganda. 3. PPE in HIV-infected Ugandan adults receiving ART for at least 15 months was associated with reported daily insect bites and greater HIV viraemia at ART commencement, independent of CD4 count. 4. Recurrent or persistent PPE in HIV-infected Ugandan adults observed over two years from initiation of ART was not associated with virological failure in participants of this study.
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Gemeniano, Maria Lourdes Charmaine. « Characterization of Orf-A of feline immunodeficiency virus / ». For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2002. http://uclibs.org/PID/11984.
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PENSIEROSO, SIMONE. « Immune reconstitution in paediatric patients with acquired immunodeficiency ». Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2008. http://hdl.handle.net/2108/611.
Texte intégralRésumé :
Background: Immune system plays a crucial role in defending organism from pathogens. However, immunological functions may be severely impaired by a number of disorders including acquired immunodeficiencies, possibly due to infections, chronic diseases, immunosuppressive drugs or surgeon therapies. In order to favour the immune reconstitution of patients with acquired immunodeficiency, various therapeutic treatments are constantly under investigation for both adults and paediatric patients.
Aim of the study: To evaluate immune reconstitution in children with acquired immunodeficiency. Attention was focused on two groups of HIV-1 vertically infected children (the first group subjected to HAART from the third months of life, the second subjected to a simplified treatment) and on a cohort of leukaemia children who underwent Umbilical Cord Blood Transplantation (UCBT).
Materials and Methods: Immune restoration was principally evaluated in terms of lymphoproliferative response and T-cell receptor (TCR) repertoire. Immunological studies were complemented by routine clinical and laboratory analyses.
Results: HIV-infected children showed a significant normalization of immune functions investigated, with a long-term maintaining of good clinical and immunological parameters. Also children who underwent UCBT showed a notable immune restoration.
Conclusions: In HIV-infected children, an early application of antiretroviral treatment from the third month of life favours immune reconstitution and the application of a simplified regimen seems to permit the maintenance of good immunological results obtained during the previous successful HAART. In the context of transplanted children our data underline applicability and advantages of UBCT compared to Bone marrow (BM) transplantations.
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Gan, Jade Ho Yue School of Biomedical Engineering UNSW. « Characterisation of bone defect models in immunodeficient animals ». Awarded by:University of New South Wales. School of Biomedical Engineering, 2005. http://handle.unsw.edu.au/1959.4/22429.
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Bone defects resulting from non-unions, fractures, significant revision joint replacements, tumour resection and osteolysis present a clinical problem. While autografts are considered the gold standard, ubiquitous use of this reparative technique is limited by graft supply and site morbidity. Recent progresses in tissue engineering using stem cells, bone enhancing molecules and gene therapy have provided more hypotheses for bone defect treatment. In vivo assessment to test these hypotheses requires animal models to mimic human conditions. Immunodeficient or nude animals have the advantage of hosting materials from human and other xenographic origins without immuno-intolerance or rejection. A thorough understanding of the biology in nude animals is vital for the further advancement of connective tissue healing and regeneration strategies. Nude mice are excellent xenographic hosts for in- vivo characterisation and provide a reproducible animal source. The immune deficiencies of nude compared to normal animals may however, influence bone healing and need to be addressed. This dissertation (a) investigated potential bone defect models in nude mice and nude rats (b) incorporated the selected bone defect model to evaluate the effect of T cell deficiency and age on bone defect healing in nude animals (c) determined the feasibility of a critical size defect (CSD) in nude mice. A distal-femur-condylar-defect (DFCD) model was successfully performed in nude mice and rats. The model was found to have some advantages as a bone defect model: (1) located at a weight-bearing skeletal site (2) no requirements for an internal or external fixator (3) does not obstruct or limit mobility (4) location is not in close proximity to any major organs such as the brain (5) easy identification of surface anatomy (6) defect size is standardised and reproducible (7) does not require lengthy and complicated surgery and (8) cost effective. This dissertation confirmed that bone healing in nude mice is similar to that of normal immunocompetent mice. Absence of T lymphocytes did not delay or inhibit bone repair. Use of older nude mice did not seem to affect the healing rate, in contrast to older normal mice, which showed delay in bone healing in the initial phase. Establishment of critical sized defects in mice at a weight-bearing location was not feasible due to the robust healing of murine. This dissertation recommends that the DFCD model could be utilized for the assessment of xenogenic materials at early time point.
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Heusinger, Elena [Verfasser]. « Preadaptation of Simian Immunodeficiency Virus SIVsmm Facilitated Env-Mediated Counteraction of Human Tetherin by Human Immunodeficiency Virus Type 2 / Elena Heusinger ». Ulm : Universität Ulm, 2019. http://d-nb.info/1177882604/34.
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Scarth, Sarah L. « Analysis of seven leukocyte adhesion deficiency (LAD) point mutations in the integrin #beta#2 subunit ». Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302071.
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Alder, Louise B. A. « Immunoregulatory properties of polyclonal immunoglobulin for therapeutic use ». Thesis, University of Newcastle Upon Tyne, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361937.
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Matthews, James Robert. « Transcriptional activation of human immunodeficiency virus type 1 by NF-κb ». Thesis, University of St Andrews, 1993. http://hdl.handle.net/10023/13981.
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This study has analysed some of the mechanisms involved in the transcriptional activation of the human immunodeficiency virus type 1 (HIV-1) by transcriptional modulator proteins of the NF-ĸB/rel family. Initial attempts to purify a single NF-ĸB (p50-p65) heterodimer species from HeLa cells suggested that a family of proteins might contribute to ĸB motif DNA binding activity. HeLa cell ĸB motif DNA binding proteins were shown to be modified by glycosylation. Using circularly permuted DNA probes carrying a KB motif, it was shown that ĸB binding proteins induced significant DNA bending upon binding, while studies of the effects of the poly amine spermidine on purified HeLa cell ĸB motif DNA binding proteins showed it greatly stimulated their DNA binding activity. The DNA binding activity of native ĸB motif DNA binding proteins was also greatly stimulated by the reducing agent dithiothreitol. Using a cDNA encoding the p105 precursor to the NF-ĸB p50 subunit, the wild type DNA binding and dimerisation region (aa35-381) of p50, and three cysteine to serine mutants at cysteine residues (aa62, 119, and 273) conserved throughout the NF-ĸB/rel/dorsal family, were expressed in bacteria. The dissociation constant of the aa62 p50 mutant for the ĸB motif was 10-fold higher than that of the wild type p50. Also, dissociation rate constants for the aa62 mutant-KB motif complex in both the presence and absence of spermidine were anomalously high. The above changes suggested a different DNA binding specificity for the aa62 mutant - this was confirmed by oligonucleotide competition studies. Oligonucleotide protection experiments suggested the presence of a cysteine residue in the p50 DNA binding site-substrate protection experiments showed that this was cysteine 62, and that this residue is involved in redox regulation of p50 DNA binding activity.
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Whiteley, Chris G., et Duu-Jong Lee. « Computer simulations of the interaction of human immunodeficiency virus (HIV) aspartic protease with spherical gold nanoparticles : implications in acquired immunodeficiency syndrome (AIDS) ». IOP Publishing Ltd, 2016. http://hdl.handle.net/10962/67083.
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publisher versionThe interaction of gold nanoparticles (AuNP) with human immune-deficiency virus aspartic protease (HIVPR) is modelled using a regime of molecular dynamics simulations. The simulations of the 'docking', first as a rigid-body complex, and eventually through flexible-fit analysis, creates 36 different complexes from four initial orientations of the nanoparticle strategically positioned around the surface of the enzyme. The structural deviations of the enzymes from the initial x-ray crystal structure during each docking simulation are assessed by comparative analysis of secondary structural elements, root mean square deviations, B-factors, interactive bonding energies, dihedral angles, radius of gyration (R g), circular dichroism (CD), volume occupied by C α , electrostatic potentials, solvation energies and hydrophobicities. Normalisation of the data narrows the selection from the initial 36 to one 'final' probable structure. It is concluded that, after computer simulations on each of the 36 initial complexes incorporating the 12 different biophysical techniques, the top five complexes are the same no matter which technique is explored. The significance of the present work is an expansion of an earlier study on the molecular dynamic simulation for the interaction of HIVPR with silver nanoparticles. This work is supported by experimental evidence since the initial 'orientation' of the AgNP with the enzyme is the same as the 'final' AuNP-HIVPR complex generated in the present study. The findings will provide insight into the forces of the binding of the HIVPR to AuNP. It is anticipated that the protocol developed in this study will act as a standard process for the interaction of any nanoparticle with any biomedical target.
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Lamrini, Hicham. « Identification and characterization of novel molecular causes of primary immunodeficiency : RELA mutations are associated to common variable immunodeficiency and systemic lupus erythematosus ». Thesis, Sorbonne Paris Cité, 2018. https://wo.app.u-paris.fr/cgi-bin/WebObjects/TheseWeb.woa/wa/show?t=2382&f=17275.
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Au-delà du bénéfice clinique du diagnostic, l'étude des patients atteints de déficits immunitaires héréditaires a aussi largement contribué à la compréhension des mécanismes moléculaires complexes impliqués dans la réponse adaptative humaine contre les pathogènes. Cependant, un grand nombre d’immunodéficiences primaires n’a pas encore été génétiquement défini, en particulier le déficit immunitaire commun variable (ou CVID en anglais). Au cours de ma thèse, j'ai cherché à identifier et caractériser de nouvelles causes moléculaires aux immunodéficiences primaires en me basant sur des mutants naturels humains comme modèle de recherche. Par séquençage entier de l'ADN de patients présentant une forme pédiatrique ou familiale de lupus érythémateux disséminé (ou SLE en anglais) et CVID, nous avons identifié trois variations hétérozygotes distinctes prédites comme délétères chez un patient atteint de CVID (RELAWT/Y306X), un patient pédiatrique SLE (RELAWT/R329X) et les patients atteints de SLE (RELAWT/H86N). Afin de comprendre comment les mutations identifiées peuvent affecter le rôle de RELA dans la voie NF-kB, nous avons confirmé que les deux mutations non-sens de RELA entraînent l'expression de formes tronquées de la protéine, tandis que la mutation faux-sens menait à l'expression de formes mutées de la protéine. Par immunoblot des protéines nucléaires et par immunofluorescence cellulaire, nous avons démontré que les deux formes tronquées de RELA peuvent entrer dans le noyau. Ensuite, en utilisant un oligonucléotide consensus NF-κB marqué, nous avons démontré que les deux formes tronquées de RELA étaient capables de se lier à l'ADN. Les trois protéines RELA mutées, lorsqu'elles étaient exprimées de manière ectopique, présentaient une altération de l'activité transcriptionnelle. Enfin, nous avons montré par co-immunoprécipitation que les trois protéines RELA mutées exprimées de manière ectopique sont capables d'interagir avec ses partenaires protéiques et de former des homodimères. En conclusion, nos résultats indiquent que des mutations affectant le facteur de transcription RELA peuvent être associées à des CVID ou des SLE. Étant donnés les cas précédents décrivant des haploinsuffisances de RELA liées à un syndrome lymphoprolifératif avec auto-immunité associé à une cytopénie auto-immune ainsi qu’aux ulcérations cutanéo-muqueuses TNF-dépendantes associées à des inflammations intestinales, notre travail élargit le spectre des maladies et des phénotypes cliniques liés à un dysfonctionnement de la protéine RELA et suggère que différentes mutations du gène RELA entraînent diverses conséquences fonctionnellesBeyond the clinical benefit for diagnosis, the study of patients with primary immunodeficiency (PID) has also largely contributed to the deciphering of the complex molecular mechanisms involved in the human adaptive response against pathogens. Still, a large number of PIDs, especially common variable immunodeficiency (CVID), are genetically not defined. During my thesis, I aimed to identify and characterize novel molecular causes of PIDs based on human natural mutants as a research model (1). By whole-exome sequencing of DNA from patients presenting either with pediatric or familial form of CVID and Systemic Lupus Erythematosus (SLE), we identified three distinct heterozygous single nucleotide variations predicted deleterious in a CVID patient (RELAY306X), a pediatric SLE patient (RELAR329X) and familial SLE patients (RELAH86N). To better understand how the identified mutations may impact the role of RELA in the NF-kB pathway, we confirmed that the two nonsense RELA mutations led to the expression of truncated forms of the protein, while the missense mutation led to the expression of mutated forms of the protein. By immunoblotting of nuclear protein extracts and cellular immunofluorescence, we demonstrated that the two truncated forms of RELA can translocate into the nucleus. Then, using a labeled NF-κB consensus oligonucleotide, we demonstrated that the two truncated forms of RELA were able to bind to DNA. All three mutated RELA proteins, when expressed ectopically, had an impaired transcriptional activity. Finally, we showed by immunoprecipitation that all three ectopically expressed mutated RELA proteins are able to interact with protein partners and form homodimers. As a whole, our results indicate that mutations affecting the transcription factor RELA can be associated with CVID or SLE. Given the previous cases associating RELA haploinsufficiency to autoimmune lymphoproliferative syndrome with autoimmune cytopenia and to TNF-dependent mucocutaneous ulceration and inflammatory intestinal disease, our work widens the spectrum of disease and clinical phenotypes associated with RELA dysfunction and suggests that different RELA mutations lead to different functional consequences
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Ollerton, Matthew T. « Capacity of Human Immunodeficiency Virus Targeting Chimeric Antigen Receptor T Cells to Eliminate Follicular Dendritic Cells Bearing Human Immunodeficiency Virus Immune Complexes ». BYU ScholarsArchive, 2017. https://scholarsarchive.byu.edu/etd/7240.
Texte intégralRésumé :
An important obstacle to a functional cure for HIV/AIDS is the persistence of viral reservoirs found throughout the body in various cells and tissues. Reservoirs can be latently infected cells, or in the case of follicular dendritic cells (FDC), non-infected cells that trap infectious virus on their surface through immune complexes (HIV-IC). Although several strategies have been employed to target and eliminate viral reservoirs, they are short-lived and ineffective. In an attempt to provide a long-term approach, chimeric antigen receptor T (CAR-T) cells were designed to eliminate native HIV on FDCs. Although effective at eliminating HIV-infected cells, and halting spreading infection, their ability to eliminate the viral reservoir found on (FDCs) remains unclear. We used a novel second-generation CAR-T cell expressing domains 1 and 2 of CD4 followed by the mannose binding lectin (MBL) to allow recognition of native HIV envelope (Env) to determine the capacity to respond to the viral reservoir found on FDCs. We employed a novel fluorescent lysis assay, the Carboxyfluorescein succinimidyl ester (CFSE) release assay, as well as flow cytometric based assays to detect functional CAR-T activation through IFN-γ production and CD107a (i.e., LAMP1) membrane accumulation to test cytolytic capacity and functional activation of CD4-MBL CAR-T cells, respectively. We demonstrated their efficacy at eliminating HIV-infected cells or cells expressing gp160. However, these CAR-T cells were unable to lyse cells bearing surface bound HIV-IC. We found that failed lysis was not a unique feature of a resistant target, but a limitation in the CAR-T recognition elements. CAR-T cells were inactive in the presence of free HIV or in the presence of concentrated, immobilized virus. Further experiments determined that in addition to gp120 recognition by the CAR-T, the adhesion molecule ICAM-1 was necessary for efficient CAR-T cell killing of HIV-infected cells. CAR-T cell activity and killing were inhibited in the presence of ICAM-1 blocking antibody. These results suggest that other factors, such as adhesion molecules, play a vital role in CAR-T responses to HIV-infected cells. In addition, our findings highlighted the necessity to consider all models of HIV reservoirs, including FDCs, when evaluating therapeutic efficacy.
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Chan, Kenneth See Kit. « Nef from pathogenic simian immunodeficiency virus attenuates vaccinia virus / ». For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2004. http://uclibs.org/PID/11984.
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Li, Yan. « Processing and secretion of human immunodeficiency virus glycoprotein,gp120 ». Thesis, University of Ottawa (Canada), 1992. http://hdl.handle.net/10393/10962.
Texte intégralRésumé :
The natural signal sequence of HIV-1 gp120 contains an unusually long hydrophobic domain and five positively charged amino acids. When the gp120 gene was cloned into a baculovirus expression vector under the control of the baculovirus polyhedrin gene promoter, it exhibited an extremely low level of secretion. However, deletion of the signal sequence resulted in the production of large quantities of a nonglycosylated form of gp120 and fusion of honeybee melittin or murine interleukin 3 signal sequences, which contain only one or no positively charged residues, respectively, resulted in a high level of expression as well as glycosylation and secretion. Four charge-altered signal mutants were generated by oligonucleotide-directed mutagenesis. Positively charged amino acids in the natural signal sequence were substituted with neutral amino acids. The results of these experiments showed that the expression and secretion of gp120 was progressively increased by decreasing the positive charge in a stepwise fashion from + 5 to + 3, + 2, and + 1. However, elimination of all five positive charges (leaving a net negative charge of -1 at the NH 2 terminus) caused accumulation of large amounts of a nonglycosylated form of gp120 but decreased the amounts of glycosylated forms of gp120. These signal peptide mutants clearly demonstrate that the positively charged amino acids in the natural signal sequence of HIV-1 gp120 are key factors determining its poor expression and secretion in insect cells. Analysis of intracellular transport and folding of gp120 further indicates that the highly charged uncleaved signal peptide rather than disulfide bond formation is an important factor limiting transport of gp120 from the rough endoplasmic reticulum (RER) to the Golgi apparatus; its presence affects gp120 folding and slows its rate of transport to the cell surface. The requirement for carbohydrate on HIV gp120 in CD4 binding has been the subject of much debate. There have been conflicting reports regarding the role of gp120 glycans in binding to CD4. An important question is whether the carbohydrate itself plays an important role in this interaction. Nonglycosylated and glycosylated forms of gp120 from HIV-1 and HIV-2 were produced using the baculovirus expression system and their CD4 binding properties were determined. The nonglycosylated forms of gp120 generated by either deletion of the signal sequence or synthesized in the presence of tunicamycin failed to bind to CD4. In contrast, highly mannosylated recombinant gp120 bound well to soluble CD4. Enzymatic removal of carbohydrate chains from glycosylated gp120 by endoglycosidase H (endo H) or by a mixture of endoglycosidase F and N-glycanase (endo FNG) in the presence or absence of SDS had little or no effect on the ability of gp120 to bind CD4. The data indicate that carbohydrate chains per se do not play a significant role in interaction between gp120 and CD4 molecules but that N-linked glycosylation is required for correct protein folding that provides the proper conformation for CD4 binding. Analysis of intracellular folding of gp120, using its ability to bind CD4 as a functional assay for overall conformation, further supports the hypothesis that N-linked glycosylation of HIV gp120 plays an essential role in promoting either the correct folding of the protein or in its stabilization.
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Zeibdawi, Abdul-Rahman. « Recombinant human immunodeficiency virus reverse transcriptases, activity and fidelity ». Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq20986.pdf.
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Yim, Chi-ho Howard. « Cytokine dysregulation by human immunodeficiency virus-1 transactivating protein ». Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B36987700.
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