Journal articles on the topic 'Protein-HIV Virus'
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1
Travis, J. "HIV Protein Prepares Virus' Next Victims." Science News 152, no. 4 (July 26, 1997): 53. http://dx.doi.org/10.2307/3981058.
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Romani, Bizhan, and Susan Engelbrecht. "Human immunodeficiency virus type 1 Vpr: functions and molecular interactions." Journal of General Virology 90, no. 8 (August 1, 2009): 1795–805. http://dx.doi.org/10.1099/vir.0.011726-0.
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Human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) is an accessory protein that interacts with a number of cellular and viral proteins. The functions of many of these interactions in the pathogenesis of HIV-1 have been identified. Deletion of the vpr gene reduces the virulence of HIV-1 dramatically, indicating the importance of this protein for the virus. This review describes the current findings on several established functions of HIV-1 Vpr and some possible roles proposed for this protein. Because Vpr exploits cellular proteins and pathways to influence the biology of HIV-1, understanding the functions of Vpr usually involves the study of cellular pathways. Several functions of Vpr are attributed to the virion-incorporated protein, but some of them are attributed to the expression of Vpr in HIV-1-infected cells. The structure of Vpr may be key to understanding the variety of its interactions. Due to the critical role of Vpr in HIV-1 pathogenicity, study of the interactions between Vpr and cellular proteins may help us to understand the mechanism(s) of HIV-1 pathogenicity.
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Álvarez, Enrique, Alfredo Castelló, Luis Menéndez-Arias, and Luis Carrasco. "HIV protease cleaves poly(A)-binding protein." Biochemical Journal 396, no. 2 (May 15, 2006): 219–26. http://dx.doi.org/10.1042/bj20060108.
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The PABP [poly(A)-binding protein] is able to interact with the 3′ poly(A) tail of eukaryotic mRNA, promoting its translation. Cleavage of PABP by viral proteases encoded by several picornaviruses and caliciviruses plays a role in the abrogation of cellular protein synthesis. We report that infection of MT-2 cells with HIV-1 leads to efficient proteolysis of PABP. Analysis of PABP integrity was carried out in BHK-21 (baby-hamster kidney) and COS-7 cells upon individual expression of the protease from several members of the Retroviridae family, e.g. MoMLV (Moloney murine leukaemia virus), MMTV (mouse mammary tumour virus), HTLV-I (human T-cell leukaemia virus type I), SIV (simian immunodeficiency virus), HIV-1 and HIV-2. Moreover, protease activity against PABP was tested in a HeLa-cell-free system. Only MMTV, HIV-1 and HIV-2 proteases were able to cleave PABP in the absence of other viral proteins. Purified HIV-1 and HIV-2 proteases cleave PABP1 directly at positions 237 and 477, separating the two first RNA-recognition motifs from the C-terminal domain of PABP. An additional cleavage site located at position 410 was detected for HIV-2 protease. These findings indicate that some retroviruses may share with picornaviruses and caliciviruses the capacity to proteolyse PABP.
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Liu, Hongmei, Xiaoyun Wu, Hongling Xiao, and John C. Kappes. "Targeting Human Immunodeficiency Virus (HIV) Type 2 Integrase Protein into HIV Type 1." Journal of Virology 73, no. 10 (October 1, 1999): 8831–36. http://dx.doi.org/10.1128/jvi.73.10.8831-8836.1999.
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ABSTRACT Integrase (IN) is the only retroviral enzyme necessary for the integration of retroviral cDNA into the host cell’s chromosomes. The structure and function of IN is highly conserved. The human immunodeficiency virus type 2 (HIV-2) IN has been shown to efficiently support 3′ processing and strand transfer of HIV-1 DNA substrate in vitro. To determine whether HIV-2 IN protein (IN2) could substitute for HIV-1 IN function in vivo, we used HIV-1 Vpr to deliver the IN2 into IN mutant HIV-1 virions by expression intrans as a Vpr-IN fusion protein.Trans-complementation with IN2 markedly increased the infectivity of IN-minus HIV-1. Compared with the homologous trans-IN protein, infectivity was increased to a level of 16%. Since IN has been found to play a role in reverse transcription (Wu et al., J. Virol. 73:2126–2135, 1999), cells infected with IN2-complemented HIV-1 were analyzed for DNA products of reverse transcription. DNA levels of approximately 18% of that of wild type were detected. The homologous trans-IN protein restored the synthesis of viral cDNA to approximately 86% of that of wild-type virus. By complementing integration-defective HIV-1 IN mutant viruses, which were not impaired in cDNA synthesis, thetrans-IN2 protein was shown to support integration up to a level of 55% compared with that of the homologoustrans-IN protein. The delivery of heterologous IN protein into HIV-1 particles in trans offers a novel approach to understand IN protein function in vivo.
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Elalouf, Amir. "In-silico Structural Modeling of Human Immunodeficiency Virus Proteins." Biomedical Engineering and Computational Biology 14 (January 2023): 117959722311544. http://dx.doi.org/10.1177/11795972231154402.
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Human immunodeficiency virus (HIV) is an infectious virus that depletes the CD4+ T lymphocytes of the immune system and causes a chronic life-treating disease—acquired immunodeficiency syndrome (AIDS). The HIV genome encodes different structural and accessory proteins involved in viral entry and life cycle. Determining the 3D structure of HIV proteins is essential for new target position finding, structure-based drug designing, and future planning for computational and laboratory experimentations. Hence, the study aims to predict the 3D structures of all the HIV structural and accessory proteins using computational homology modeling to understand better the structural basis of HIV proteins interacting with host cells and viral replication. The sequences of HIV capsid, matrix, nucleocapsid, p6, reverse transcriptase, invertase, protease, gp120, gp41, virus protein r, viral infectivity factor, virus protein unique, RNA splicing regulator, transactivator protein, negative regulating factor, and virus protein x proteins were retrieved from UniProt. The primary and secondary structures of HIV proteins were predicted by Expasy ProtParam and SOPMA web servers. For the homology modeling, the MODELLER predicted the 3D structures of HIV proteins using templates. Then, the modeled structures were validated by the Ramachandran plot, local and global quality estimation scores, QMEAN scores, and Z-scores. Most of the amino acid residues of HIV proteins were present in the most favored and generously allowed regions in the Ramachandran plots. The local and global quality scores and Z-scores of the HIV proteins confirmed the good quality of modeled structures. The 3D modeled structures of HIV proteins might help further investigate the possible treatment.
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Coghlan, Andy. "Virus-sabotaging protein may help people defy HIV." New Scientist 220, no. 2940 (October 2013): 19. http://dx.doi.org/10.1016/s0262-4079(13)62520-8.
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Tang, Yao, Ulrike Winkler, Eric O. Freed, Ted A. Torrey, Wankee Kim, Henry Li, Stephen P. Goff, and Herbert C. Morse. "Cellular Motor Protein KIF-4 Associates with Retroviral Gag." Journal of Virology 73, no. 12 (December 1, 1999): 10508–13. http://dx.doi.org/10.1128/jvi.73.12.10508-10513.1999.
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ABSTRACT Previously we demonstrated that murine retroviral Gag proteins associate with a cellular motor protein, KIF-4. Using the yeast two-hybrid assay, we also found an association of KIF-4 with Gag proteins of Mason-Pfizer monkey virus (MPMV), simian immunodeficiency virus (SIV), and human immunodeficiency virus type 1 (HIV-1). Studies performed with mammalian cell systems confirmed that the HIV-1 Gag protein associates with KIF-4. Soluble cytoplasmic proteins from cells infected with recombinant vaccinia virus expressing the entire Gag-Pol precursor protein of HIV-1 or transfected with HIV-1 molecular clone pNL4-3 were fractionated by sucrose gradient centrifugation and further separated by size-exclusion and anion-exchange chromatographies. KIF-4 and HIV-1 Gag cofractionated in both chromatographic separations. Immunoprecipitation assays have also verified the KIF-4–Gag association. KIF-4 binds mainly to the Gag precursor (Pr55 Gag) and a matrix-capsid processing intermediate (Pr42) but not to other processed Gag products. The binding of Gag is mediated by a domain of KIF-4 proximal to the C terminus. These results, and our previous studies, raise the possibility that KIF-4 may play an important role in retrovirus Gag protein transport.
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Noble, Beth, Paolo Abada, Juan Nunez-Iglesias, and Paula M. Cannon. "Recruitment of the Adaptor Protein 2 Complex by the Human Immunodeficiency Virus Type 2 Envelope Protein Is Necessary for High Levels of Virus Release." Journal of Virology 80, no. 6 (March 15, 2006): 2924–32. http://dx.doi.org/10.1128/jvi.80.6.2924-2932.2006.
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ABSTRACT The envelope (Env) protein of human immunodeficiency virus type 2 (HIV-2) and the HIV-1 Vpu protein stimulate the release of retroviral particles from human cells that restrict virus production, an activity that we call the enhancement of virus release (EVR). We have previously shown that two separate domains in the HIV-2 envelope protein are required for this activity: a glycine-tyrosine-x-x-hydrophobic (GYxxθ) motif in the cytoplasmic tail and an unmapped region in the ectodomain of the protein. We here report that the cellular partner of the GYxxθ motif is the adaptor protein complex AP-2. The mutation of this motif or the depletion of AP-2 by RNA interference abrogated EVR activity and changed the cellular distribution of the Env from a predominantly punctate pattern to a more diffuse distribution. Since the L domain of equine infectious anemia virus (EIAV) contains a Yxxθ motif that interacts with AP-2, we used both wild-type and L domain-defective particles of HIV-1 and EIAV to examine whether the HIV-2 Env EVR function was analogous to L domain activity. We observed that the production of all particles was stimulated by HIV-2 Env or Vpu, suggesting that the L domain and EVR activities play independent roles in the release of retroviruses. Interestingly, we found that the cytoplasmic tail of the murine leukemia virus (MLV) Env could functionally substitute for the HIV-2 Env tail, but it did so in a manner that did not require a Yxxθ motif or AP-2. The cellular distribution of the chimeric HIV-2/MLV Env was significantly less punctate than the wild-type Env, although confocal analysis revealed an overlap in the steady-state locations of the two proteins. Taken together, these data suggest that the essential GYxxθ motif in the HIV-2 Env tail recruits AP-2 in order to direct Env to a cellular pathway or location that is necessary for its ability to enhance virus release but that an alternate mechanism provided by the MLV Env tail can functionally substitute.
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Fackler, Oliver T., Paola d'Aloja, Andreas S. Baur, Maurizio Federico, and B. Matija Peterlin. "Nef from Human Immunodeficiency Virus Type 1F12 Inhibits Viral Production and Infectivity." Journal of Virology 75, no. 14 (July 15, 2001): 6601–8. http://dx.doi.org/10.1128/jvi.75.14.6601-6608.2001.
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ABSTRACT Human immunodeficiency virus type 1F12(HIV-1F12) interferes with the replication of other strains of HIV. Its accessory protein, Nef, is sufficient for this phenotype, where the production and infectivity of HIV are impaired significantly. The analysis of three rare mutations in this Nef protein revealed that these effects could be separated genetically. Moreover, the defect in virus production correlated with the lack of processing of the p55Gag precursor in the presence of Nef from HIV-1F12. Importantly, the introduction of one of these mutations (E177G) into Nef from HIV-1NL4-3 also created a dominant-negative Nef protein. Effects of Nef from HIV-1F12on virus production and Gag processing correlated with its altered subcellular distribution. Moreover, the association with two new cellular proteins with molecular masses of 74 and 75 kDa, which do not interact with other Nef proteins, correlated with the decreased virion infectivity. The identification of a dominant-negative protein for the production and infectivity of HIV suggests that Nef plays an active role at this stage of the viral replicative cycle.
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Meschi, Joseph, Erika C. Crouch, Paul Skolnik, Khabirah Yahya, Uffe Holmskov, Rikke Leth-Larsen, Ida Tornoe, Tesfaldet Tecle, Mitchell R. White, and Kevan L. Hartshorn. "Surfactant protein D binds to human immunodeficiency virus (HIV) envelope protein gp120 and inhibits HIV replication." Journal of General Virology 86, no. 11 (November 1, 2005): 3097–107. http://dx.doi.org/10.1099/vir.0.80764-0.
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The envelope protein (gp120) of human immunodeficiency virus (HIV) contains highly conserved mannosylated oligosaccharides. These glycoconjugates contribute to resistance to antibody neutralization, and binding to cell surface lectins on macrophages and dendritic cells. Mannose-binding lectin (MBL) binds to gp120 and plays a role in defence against the virus. In this study it is demonstrated that surfactant protein D (SP-D) binds to gp120 and inhibits HIV infectivity at significantly lower concentrations than MBL. The binding of SP-D was mediated by its calcium-dependent carbohydrate-binding activity and was dependent on glycosylation of gp120. Native dodecameric SP-D bound to HIV gp120 more strongly than native trimeric SP-D. Since one common polymorphic form of SP-D is predominantly expressed as trimers and associated with lower blood levels, these individuals may have less effective innate defence against HIV. A chimeric protein containing the N-terminal and collagen domains of SP-D linked to the neck and carbohydrate-recognition domains of MBL (called SP-D/MBLneck+CRD) had greater ability to bind to gp120 and inhibit virus replication than either SP-D or MBL. The enhanced binding of SP-D/MBLneck+CRD was dependent on assembly into higher molecular mass multimers (i.e. a trimeric form of the chimera did not bind to a greater extent than MBL). Hence, the enhanced binding of SP-D compared with MBL results from distinctive properties of its N-terminal and/or collagen domains. SP-D is present in lung and airway fluids, as well as in blood and various mucosal locations, and could, like MBL, play a role in restricting HIV transmission or replication in vivo.
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Villet, Stéphanie, Baya Amel Bouzar, Thierry Morin, Gérard Verdier, Catherine Legras, and Yahia Chebloune. "Maedi-Visna Virus and Caprine Arthritis Encephalitis Virus Genomes Encode a Vpr-Like but No Tat Protein." Journal of Virology 77, no. 17 (September 1, 2003): 9632–38. http://dx.doi.org/10.1128/jvi.77.17.9632-9638.2003.
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ABSTRACT A small open reading frame (ORF) in maedi-visna virus (MVV) and caprine arthritis encephalitis virus (CAEV) was initially named “tat” by analogy with a similarly placed ORF in the primate lentiviruses. The encoded “Tat” protein was ascribed the function of up regulation of the viral transcription from the long terminal repeat (LTR) promoter, but we have recently reported that MVV and CAEV Tat proteins lack trans-activation function activity under physiological conditions (S. Villet, C. Faure, B. Bouzar, G. Verdien, Y. Chebloune, and C. Legras, Virology 307:317-327, 2003). In the present work, we show that MVV Tat localizes to the nucleus of transfected cells, probably through the action of a nuclear localization signal in its C-terminal portion. We also show that, unlike the human immunodeficiency virus (HIV) Tat protein, MVV Tat was not secreted into the medium by transfected human or caprine cells in the absence of cell lysis but that, like the primate accessory protein Vpr, MVV and CAEV Tat proteins were incorporated into viral particles. In addition, analysis of the primary protein structures showed that small-ruminant lentivirus (SRLV) Tat proteins are more similar to the HIV type 1 (HIV-1) Vpr protein than to HIV-1 Tat. We also demonstrate a functional similarity between the SRLV Tat proteins and the HIV-1 Vpr product in the induction of a specific G2 arrest of the cell cycle in MVV Tat-transfected cells, which increases the G2/G1 ratio 2.8-fold. Together, these data strongly suggest that the tat ORF in the SRLV genomes does not code for a regulatory transactivator of the LTR but, rather, for a Vpr-like accessory protein.
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Conti, Lucia, Barbara Varano, M. Cristina Gauzzi, Paola Matarrese, Maurizio Federico, Walter Malorni, Filippo Belardelli, and Sandra Gessani. "Impairment of Human Immunodeficiency Virus Type 1 (HIV-1) Entry into Jurkat T Cells by Constitutive Expression of the HIV-1 Vpr Protein: Role of CD4 Down-Modulation." Journal of Virology 74, no. 21 (November 1, 2000): 10207–11. http://dx.doi.org/10.1128/jvi.74.21.10207-10211.2000.
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ABSTRACT Jurkat T-cell clones, stably expressing the human immunodeficiency virus type 1 (HIV-1) Vpr protein, exhibited an impaired susceptibility to HIV-1 infection. A marked down-modulation of surface CD4 receptors was detected in Vpr-expressing clones with respect to control cells. Likewise, a reduced CD4 expression was also observed in parental Jurkat cells infected with wild-type but not with Vpr-mutant HIV-1. Notably, Vpr-expressing clones were fully susceptible to infection with a vesicular stomatitis virus G protein-pseudotyped HIV-1 virus, indicating that a block at the level of viral entry was responsible for the inhibition of viral replication. The effect exerted by Vpr on HIV replication and CD4 expression suggests that this protein can regulate both the establishment of a productive HIV-1 infection and CD4-mediated T-cell functions.
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Abada, Paolo, Beth Noble, and Paula M. Cannon. "Functional Domains within the Human Immunodeficiency Virus Type 2 Envelope Protein Required To Enhance Virus Production." Journal of Virology 79, no. 6 (March 15, 2005): 3627–38. http://dx.doi.org/10.1128/jvi.79.6.3627-3638.2005.
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ABSTRACT Primate lentiviruses code for a protein that stimulates virus production. In human immunodeficiency virus type 1 (HIV-1), the activity is provided by the accessory protein, Vpu, while in HIV-2 and simian immunodeficiency virus it is a property of the envelope (Env) glycoprotein. Using a group of diverse retroviruses and cell types, we have confirmed the functional equivalence of the two proteins. However, despite these similarities, the two proteins have markedly different functional domains. While the Vpu activity is associated primarily with its membrane-spanning region, we have determined that the HIV-2 Env activity requires both the cytoplasmic tail and ectodomain of the protein, with the membrane-spanning domain being less important. Within the Env cytoplasmic tail, we further defined the necessary sequence as a membrane-proximal tyrosine-based motif. Providing the two Env regions separately as distinct CD8 chimeric proteins did not increase virus release. This suggests that the two domains must be either contained within a single protein or closely associated within a multiprotein oligomer, such as the Env trimer, in order to function. Finally, we observed that wild-type levels of incorporation of the HIV-2 Env into budding viruses were not required for this activity.
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Chan, Eric Y., Jennifer N. Sutton, Jon M. Jacobs, Andrey Bondarenko, Richard D. Smith, and Michael G. Katze. "Dynamic Host Energetics and Cytoskeletal Proteomes in Human Immunodeficiency Virus Type 1-Infected Human Primary CD4 Cells: Analysis by Multiplexed Label-Free Mass Spectrometry." Journal of Virology 83, no. 18 (July 8, 2009): 9283–95. http://dx.doi.org/10.1128/jvi.00814-09.
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ABSTRACT We report on a proteomic analysis of ex vivo human immunodeficiency virus (HIV) type 1 infection in human primary CD4 cells by shotgun liquid chromatography-tandem mass spectrometry analysis, revealing two distinct proteomic profiles at two phases of virus replication. Relative to mock-infected cells, 168 signature proteins exhibited abundance changes at the first sign of Gag p24 production (8 h postinfection [p.i.]) or the peak of virus replication (24 h p.i.); interestingly, most of the changes were exclusive to only one phase of virus replication. Based on characterization by functional ontology and known human-HIV protein interactions, we observed the enrichment for protein abundance increases pertaining to protein synthesis and nucleasomal reorganization amid an otherwise placid cellular proteome at the first sign of HIV replication. In contrast, we observed indications of decreased protein turnover, concomitant with heightened DNA repair activities and preludes to apoptosis, in the presence of robust virus replication. We also observed hints of disruptions in protein and small molecule trafficking. Our label-free proteomic strategy allowed us to perform multiplexed comparisons—we buttressed our detection specificity with the use of a reverse transcriptase inhibitor as a counterscreen, enabling highlighting of cellular protein abundance changes unique to robust virus replication as opposed to viral entry. In conjunction with complementary high-throughput screens for cellular partners of HIV, we put forth a model pinpointing specific rerouting of cellular biosynthetic, energetic, and trafficking pathways as HIV replication accelerates in human primary CD4 cells.
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Wang, Bao-Zhong, Weimin Liu, Sang-Moo Kang, Munir Alam, Chunzi Huang, Ling Ye, Yuliang Sun, et al. "Incorporation of High Levels of Chimeric Human Immunodeficiency Virus Envelope Glycoproteins into Virus-Like Particles." Journal of Virology 81, no. 20 (August 1, 2007): 10869–78. http://dx.doi.org/10.1128/jvi.00542-07.
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ABSTRACT The human immunodeficiency virus (HIV) envelope (Env) protein is incorporated into HIV virions or virus-like particles (VLPs) at very low levels compared to the glycoproteins of most other enveloped viruses. To test factors that influence HIV Env particle incorporation, we generated a series of chimeric gene constructs in which the coding sequences for the signal peptide (SP), transmembrane (TM), and cytoplasmic tail (CT) domains of HIV-1 Env were replaced with those of other viral or cellular proteins individually or in combination. All constructs tested were derived from HIV type 1 (HIV-1) Con-S ΔCFI gp145, which itself was found to be incorporated into VLPs much more efficiently than full-length Con-S Env. Substitution of the SP from the honeybee protein mellitin resulted in threefold-higher chimeric HIV-1 Env expression levels on insect cell surfaces and an increase of Env incorporation into VLPs. Substitution of the HIV TM-CT with sequences derived from the mouse mammary tumor virus (MMTV) envelope glycoprotein, influenza virus hemagglutinin, or baculovirus (BV) gp64, but not from Lassa fever virus glycoprotein, was found to enhance Env incorporation into VLPs. The highest level of Env incorporation into VLPs was observed in chimeric constructs containing the MMTV and BV gp64 TM-CT domains in which the Gag/Env molar ratios were estimated to be 4:1 and 5:1, respectively, compared to a 56:1 ratio for full-length Con-S gp160. Electron microscopy revealed that VLPs with chimeric HIV Env were similar to HIV-1 virions in morphology and size and contained a prominent layer of Env spikes on their surfaces. HIV Env specific monoclonal antibody binding results showed that chimeric Env-containing VLPs retained conserved epitopes and underwent conformational changes upon CD4 binding.
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Alatortseva, G. I., M. N. Nosik, L. N. Nesterenko, I. I. Amiantova, V. V. Dotsenko, L. N. Luhverchik, M. V. Zhuckina, V. U. Kabargina, E. N. Kudryavtseva, and V. V. Zverev. "Study of Antigenic properties of Human immunodeficiency Virus NEF protein Recombinant Analog." Epidemiology and Vaccine Prevention 15, no. 3 (June 20, 2016): 83–93. http://dx.doi.org/10.31631/2073-3046-2016-15-3-83-93.
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Protein p27/p25 is a product of HIV nef gene and is a multifunctional factor of HIV pathogenicity. Antigenic properties of recombinant NEF polypeptide which includes N-terminal fragment of HIV-1 p27 protein fused to E. coli ß-galactosidase were studied by serological and virological methods. The interaction was shown between recombinant NEF antigen and serums of HIV-positive individuals by ELISA, Western blot and line immunoassay. There was no interaction with sera of healthy individuals. The antigen specificity of recombinant antigen was shown in the reactions with commercial HIV-1 p27/p25 protein analog and with polyclonal antibodies to synthetic peptides corresponding to N-, C-terminal regions of HIV-1 p27/p25 protein. The interaction between IgG of rabbits immunized with recombinant NEF antigen and viral antigens was shown by indirect immunofluorescence and neutralizing assays. Thus it was proven the possibility of using recombinant NEF protein as an antigen for diagnostic and experimental purposes.
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Griffin, Stephen D. C., Jane F. Allen, and Andrew M. L. Lever. "The Major Human Immunodeficiency Virus Type 2 (HIV-2) Packaging Signal Is Present on All HIV-2 RNA Species: Cotranslational RNA Encapsidation and Limitation of Gag Protein Confer Specificity." Journal of Virology 75, no. 24 (December 15, 2001): 12058–69. http://dx.doi.org/10.1128/jvi.75.24.12058-12069.2001.
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ABSTRACT Deletion of a region of the human immunodeficiency virus type 2 (HIV-2) 5′ leader RNA reduces genomic RNA encapsidation to about 5% that of wild-type virus with no defect in viral protein production but severely limits virus spread in Jurkat T cells, indicating that this region contains a major cis-acting encapsidation signal, or psi (Ψ). Being upstream of the major splice donor, it is present on all viral transcripts. We have shown that HIV-2 selects its genomic RNA for encapsidation cotranslationally, rendering wild-type HIV-2 unable to encapsidate vector RNAs in trans . Virus with Ψ deleted, however, encapsidates an HIV-2 vector, demonstrating competition for Gag protein. HIV-2 overcomes the lack of packaging signal location specificity by two novel mechanisms, cotranslational packaging and competition for limiting Gag polyprotein.
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Chazal, Nathalie, Gregory Singer, Christopher Aiken, Marie-Louise Hammarskjöld, and David Rekosh. "Human Immunodeficiency Virus Type 1 Particles Pseudotyped with Envelope Proteins That Fuse at Low pH No Longer Require Nef for Optimal Infectivity." Journal of Virology 75, no. 8 (April 15, 2001): 4014–18. http://dx.doi.org/10.1128/jvi.75.8.4014-4018.2001.
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ABSTRACT We have investigated the effects of Nef on infectivity in the context of various viral envelope proteins. These experiments were performed with a minimal vector system where Nef is the only accessory protein present. Our results support the hypothesis that the route of entry influences the ability of Nef to enhance human immunodeficiency virus (HIV) infectivity. We show that HIV particles pseudotyped with Ebola virus glycoprotein or vesicular stomatitis virus glycoprotein (VSV-G), which fuse at low pH, do not require Nef for optimal infectivity. In contrast, Nef significantly enhances the infectivity of virus particles that contain envelope proteins that fuse at neutral pH (CCR5-dependent HIV Env, CXCR4-dependent HIV Env, or amphotropic murine leukemia virus Env). In addition, our results demonstrate that virus particles containing mixed CXCR4-dependent HIV and VSV-G envelope proteins show a conditional requirement for Nef for optimal infectivity, depending on which protein is allowed to facilitate entry.
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Copeland, K. M., A. J. Elliot, and R. S. Daniels. "Functional Chimeras of Human Immunodeficiency Virus Type 1 gp120 and Influenza A Virus (H3) Hemagglutinin." Journal of Virology 79, no. 10 (May 15, 2005): 6459–71. http://dx.doi.org/10.1128/jvi.79.10.6459-6471.2005.
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ABSTRACT In an attempt to produce a protein that will allow determination of the native human immunodeficiency virus type 1 (HIV-1) gp120 (Env) structure in its trimeric state, we fused the globular head of gp120 to the stalk region of influenza virus A (X31) hemagglutinin (HA). The chimeric protein (EnvHA) has been expressed by using a recombinant vaccinia virus system, and its functional characteristics were determined. EnvHA is expressed as a 120- to 150-kDa protein that can oligomerize to form dimers and trimers. It retains the low-pH (5.2 to 5.4) requirement of X31-HA to trigger membrane fusion but, unlike X31-HA, it is not absolutely dependent on exogenously added trypsin for protein processing to release the HA2 fusion peptide. In terms of receptor binding the chimeric protein retains specificity for human CD4 but, in relation to the membrane fusion event, it appears to lose the Env coreceptor specificity of the parental HIV-1 strains: NL43 for CXCR4 and JRFL for CCR5. These properties suggest that stable, functional EnvHAs are being produced and that they may be exploited in terms of structural studies. Further, the potential of introducing the envHA genes into influenza viruses, by use of reverse genetics, and their use as a therapeutic vaccine for HIV are discussed.
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Feng, Feng, Adam Davis, Julie-Anne Lake, Jill Carr, Wei Xia, Christopher Burrell, and Peng Li. "Ring Finger Protein ZIN Interacts with Human Immunodeficiency Virus Type 1 Vif." Journal of Virology 78, no. 19 (October 1, 2004): 10574–81. http://dx.doi.org/10.1128/jvi.78.19.10574-10581.2004.
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ABSTRACT Virion infectivity factor (Vif) protein of human immunodeficiency virus type 1 (HIV-1) is essential for the productive infection of primary human CD4 T lymphocytes and macrophages. Vif overcomes the HIV-inhibitory effects of cellular factor APOBEC3G, which has cytidine deaminase activity. We previously reported the isolation of a Vif-interacting ring finger protein, Triad 3, from a human leukocyte cDNA library, using the yeast two-hybrid system. The full-length cellular protein homologue of Triad 3 has been recently identified as the zinc finger protein inhibiting NF-κB (ZIN). Sequence analysis indicates that Triad 3 protein contains all four major ring-like motifs of ZIN. We report here that ZIN binds to purified Vif in vitro and that Triad 3/ZIN interacts with HIV-1 Vif in transfected human 293T cells, as demonstrated by coimmunoprecipitation. To test the biological relevance of this interaction, we produced infectious HIV-1 NL4.3 in the presence or absence of cotransfected ZIN. HIV-1 NL4.3 virus stocks produced in the presence of exogenously expressed ZIN were twofold less infectious in a single-cycle infectivity assay than virus produced in the absence of exogenous ZIN. It was further shown that cells infected with HIV NL4.3 virus stocks produced in the presence of exogenously expressed ZIN were impaired in viral DNA synthesis by twofold. The impairment in viral reverse transcription and the reduction in single-cycle viral infectivity were both shown to be dependent on the presence of Vif in the virus producer cells. The possible mechanisms by which ZIN interferes with the early events of HIV-1 replication are discussed.
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Stevens, Miguel, Christophe Pannecouque, Erik De Clercq, and Jan Balzarini. "Novel Human Immunodeficiency Virus (HIV) Inhibitors That Have a Dual Mode of Anti-HIV Action." Antimicrobial Agents and Chemotherapy 47, no. 10 (October 2003): 3109–16. http://dx.doi.org/10.1128/aac.47.10.3109-3116.2003.
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ABSTRACT We have found that novel pyridine oxide derivatives are inhibitors of a wide range of human immunodeficiency virus (HIV) type 1 (HIV-1) and HIV-2 strains in CEM cell cultures. Some of the compounds showed inhibitory activities against recombinant HIV-1 reverse transcriptase (RT), whereas others were totally inactive against this viral protein in vitro. Partial retention of anti-HIV-1 activity against virus strains that contain a variety of mutations characteristic of those for resistance to nonnucleoside RT inhibitors and a lack of inhibitory activity against recombinant HIV-2 RT suggested that these pyridine oxide derivatives possess a mode of antiviral action independent from HIV RT inhibition. Time-of-addition experiments revealed that these pyridine oxide derivatives interact at a postintegration step in the replication cycle of HIV. Furthermore, it was shown that these compounds are active not only in acutely HIV-1-infected cells but also in chronically HIV-infected cells. A dose-dependent inhibition of virus particle release and viral protein expression was observed upon exposure to the pyridine oxide derivatives. Finally, inhibition of HIV-1 long terminal repeat-mediated green fluorescence protein expression in quantitative transactivation bioassays indicated that the additional target of action of the pyridine oxide derivatives may be located at the level of HIV gene expression.
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Ewart, Gary D., Najla Nasr, Hassan Naif, Graeme B. Cox, Anthony L. Cunningham, and Peter W. Gage. "Potential New Anti-Human Immunodeficiency Virus Type 1 Compounds Depress Virus Replication in Cultured Human Macrophages." Antimicrobial Agents and Chemotherapy 48, no. 6 (June 2004): 2325–30. http://dx.doi.org/10.1128/aac.48.6.2325-2330.2004.
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ABSTRACT We report that the amiloride analogues 5-(N,N-hexamethylene)amiloride and 5-(N,N-dimethyl)amiloride inhibit, at micromolar concentrations, the replication of human immunodeficiency virus type 1 (HIV-1) in cultured human blood monocyte-derived macrophages. These compounds also inhibit the in vitro activities of the HIV-1 Vpu protein and might represent lead compounds for a new class of anti-HIV-1 drugs.
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Murakami, Hironobu, Takehiro Suzuki, Kiyoto Tsuchiya, Hiroyuki Gatanaga, Manabu Taura, Eriko Kudo, Seiji Okada, et al. "Protein Arginine N-methyltransferases 5 and 7 Promote HIV-1 Production." Viruses 12, no. 3 (March 23, 2020): 355. http://dx.doi.org/10.3390/v12030355.
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Current therapies for human immunodeficiency virus type 1 (HIV-1) do not completely eliminate viral reservoirs in cells, such as macrophages. The HIV-1 accessory protein viral protein R (Vpr) promotes virus production in macrophages, and the maintenance of Vpr is essential for HIV-1 replication in these reservoir cells. We identified two novel Vpr-binding proteins, i.e., protein arginine N-methyltransferases (PRMTs) 5 and 7, using human monocyte-derived macrophages (MDMs). Both proteins found to be important for prevention of Vpr degradation by the proteasome; in the context of PRMT5 and PRMT7 knockdowns, degradation of Vpr could be prevented using a proteasome inhibitor. In MDMs infected with a wild-type strain, knockdown of PRMT5/PRMT7 and low expression of PRMT5 resulted in inefficient virus production like Vpr-deficient strain infections. Thus, our findings suggest that PRMT5 and PRMT7 support HIV-1 replication via maintenance of Vpr protein stability.
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Mete, Bilgül, Emre Pekbilir, Bilge Nur Bilge, Panagiota Georgiadou, Elif Çelik, Tolga Sutlu, Fehmi Tabak, and Umut Sahin. "Human immunodeficiency virus type 1 impairs sumoylation." Life Science Alliance 5, no. 6 (February 18, 2022): e202101103. http://dx.doi.org/10.26508/lsa.202101103.
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During infection, the human immunodeficiency virus type 1 (HIV-1) manipulates host cell mechanisms to its advantage, thereby controlling its replication or latency, and evading immune responses. Sumoylation is an essential post-translational modification that controls vital cellular activities including proliferation, stemness, or anti-viral immunity. SUMO peptides oppose pathogen replication and mediate interferon-dependent anti-viral activities. In turn, several viruses and bacteria attack sumoylation to disarm host immune responses. Here, we show that HIV-1 impairs cellular sumoylation and targets the host SUMO E1–activating enzyme. HIV-1 expression in cultured HEK293 cells or in CD4+ Jurkat T lymphocytes diminishes sumoylation by both SUMO paralogs, SUMO1 and SUMO2/3. HIV-1 causes a sharp and specific decline in UBA2 protein levels, a subunit of the heterodimeric SUMO E1 enzyme, which likely serves to reduce the efficiency of global protein sumoylation. Furthermore, HIV-1–infected individuals display a significant reduction in total leukocyte sumoylation that is uncoupled from HIV-induced cytopenia. Because sumoylation is vital for immune function, T-cell expansion and activity, loss of sumoylation during HIV disease may contribute to immune system deterioration in patients.
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Padow, Marcus, Lilin Lai, Champion Deivanayagam, Lawrence J. DeLucas, Robert B. Weiss, Diane M. Dunn, Xiaoyun Wu, and John C. Kappes. "Replication of Chimeric Human Immunodeficiency Virus Type 1 (HIV-1) Containing HIV-2 Integrase (IN): Naturally Selected Mutations in IN Augment DNA Synthesis." Journal of Virology 77, no. 20 (October 15, 2003): 11050–59. http://dx.doi.org/10.1128/jvi.77.20.11050-11059.2003.
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ABSTRACT The human immunodeficiency virus type 1 (HIV-1) integrase (IN) protein augments the initiation of reverse transcription. Chimeric HIV-1 containing HIV-2 IN (SG3IN2) is severely impaired in virus infectivity and DNA synthesis. To analyze the nature of this defect, we infected T cells with the chimeric SG3IN2 virus and by continuous passage in cell culture selected for virus with improved replication properties. Viruses from two different time points were chosen for further analysis, an early culture-adapted virus (CF-65) that exhibited an intermediate level of infectivity, and a later-passaged virus (CF-131) that was significantly more infectious. Sequence analysis of multiple clones derived from the CF-65 virus culture demonstrated a diversity of mutations in the reverse transcriptase (RT) and a common V204I IN mutation. Analysis of clones derived from the CF-131 virus indicated the selection of two additional IN mutations, Q96H and K127E, and a fixed V179I RT mutation. By cloning RT and/or IN sequences back into the original SG3IN2 chimeric virus, we demonstrated that mutations in both RT and IN contributed to the improvement in viral fitness. The effect of the HIV-2IN(IN2) mutations on virus DNA synthesis was analyzed by packaging IN2 mutants into HIV-1 as Vpr-IN2 fusion proteins. This analysis revealed that the Q96H, K127E and V204I mutations increased the infectivity of the chimeric virus by augmenting the initiation of viral cDNA synthesis in infected cells. The Q96H and K127E mutations are present in adjacent helical structures on the surface of the IN protein and together account for most of the increase observed in DNA synthesis. Our findings provide evidence that the IN protein augments the initiation of reverse transcription through specific interactions with other viral components comprising the initiation complex. Moreover, they implicate specific regions on the surface of IN that may help to elucidate mechanisms by which the HIV-1 IN protein augments the initiation of HIV-1 reverse transcription in vivo.
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Zhou, Jing, and Christopher Aiken. "Nef Enhances Human Immunodeficiency Virus Type 1 Infectivity Resulting from Intervirion Fusion: Evidence Supporting a Role for Nef at the Virion Envelope." Journal of Virology 75, no. 13 (July 1, 2001): 5851–59. http://dx.doi.org/10.1128/jvi.75.13.5851-5859.2001.
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ABSTRACT The human immunodeficiency virus type 1 (HIV-1) accessory protein Nef stimulates viral infectivity by facilitating an early event in the HIV-1 life cycle. Although no structural or biochemical defects in Nef-defective HIV-1 particles have been demonstrated, the Nef protein is incorporated into HIV-1 particles. To localize the function of Nef within the virus particle, we developed a novel technology involving fusion of enveloped donor HIV-1 particles bearing core defects with envelope-defective target virions bearing HIV-1 receptors. Although neither virus alone was capable of infecting CD4+ target cells, the incubation of donor and target virions prior to addition to target cells resulted in infection. This effect, termed “virion transcomplementation,” required a functional Env protein on the donor virus and CD4 and an appropriate coreceptor on target virions. To provide evidence for intervirion fusion as the mechanism of complementation, experiments were performed using dual-enveloped HIV-1 particles bearing both HIV-1 and ecotropic murine leukemia virus (E-MLV) Env proteins as donor virions. Infection of CD4-negative target cells bearing E-MLV receptors was prevented by HIV-1 entry inhibitors when added before, but not after, incubation of donor and target virions prior to the addition to cells. When we used Nef+and Nef− donor and target virions, Nef enhanced infection when present in donor virions. In contrast, no effect of Nef was detected when present in the target virus. These results reveal a potential mechanism for enhancing HIV-1 diversity in vivo through the rescue of defective viral genomes and provide a novel genetic system for the functional analysis of virion-associated proteins in HIV-1 infection.
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McLinden, James H., Jack T. Stapleton, Donna Klinzman, Krishna K. Murthy, Qing Chang, Thomas M. Kaufman, Nirjal Bhattarai, and Jinhua Xiang. "Chimpanzee GB virus C and GB virus A E2 envelope glycoproteins contain a peptide motif that inhibits human immunodeficiency virus type 1 replication in human CD4+ T-cells." Journal of General Virology 94, no. 4 (April 1, 2013): 774–82. http://dx.doi.org/10.1099/vir.0.047126-0.
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GB virus type C (GBV-C) is a lymphotropic virus that can cause persistent infection in humans. GBV-C is not associated with any disease, but is associated with reduced mortality in human immunodeficiency virus type 1 (HIV-1)-infected individuals. Related viruses have been isolated from chimpanzees (GBV-Ccpz) and from New World primates (GB virus type A, GBV-A). These viruses are also capable of establishing persistent infection. We determined the nucleotide sequence encoding the envelope glycoprotein (E2) of two GBV-Ccpz isolates obtained from the sera of captive chimpanzees. The deduced GBV-Ccpz E2 protein differed from human GBV-C by 31 % at the amino acid level. Similar to human GBV-C E2, expression of GBV-Ccpz E2 in a tet-off human CD4+ Jurkat T-cell line significantly inhibited the replication of diverse HIV-1 isolates. This anti-HIV-replication effect of GBV-Ccpz E2 protein was reversed by maintaining cells in doxycycline to reduce E2 expression. Previously, we found a 17 aa region within human GBV-C E2 that was sufficient to inhibit HIV-1. Although GBV-Ccpz E2 differed by 3 aa differences in this region, the chimpanzee GBV-C 17mer E2 peptide inhibited HIV-1 replication. Similarly, the GBV-A peptide that aligns with this GBV-C E2 region inhibited HIV-1 replication despite sharing only 5 aa with the human GBV-C E2 sequence. Thus, despite amino acid differences, the peptide region on both the GBV-Ccpz and the GBV-A E2 protein inhibit HIV-1 replication similar to human GBV-C. Consequently, GBV-Ccpz or GBV-A infection of non-human primates may provide an animal model to study GB virus–HIV interactions.
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Ali, Amjad, Rameez Raja, Sabihur Rahman Farooqui, Shaista Ahmad, and Akhil C. Banerjea. "USP7 deubiquitinase controls HIV-1 production by stabilizing Tat protein." Biochemical Journal 474, no. 10 (May 4, 2017): 1653–68. http://dx.doi.org/10.1042/bcj20160304.
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Deubiquitinases (DUBs) are key regulators of complex cellular processes. HIV-1 Tat is synthesized early after infection and is mainly responsible for enhancing viral production. Here, we report that one of the DUBs, USP7, stabilized the HIV-1 Tat protein through its deubiquitination. Treatment with either a general DUB inhibitor (PR-619) or USP7-specific inhibitor (P5091) resulted in Tat protein degradation. The USP7-specific inhibitor reduced virus production in a latently infected T-lymphocytic cell line J1.1, which produces large amounts of HIV-1 upon stimulation. A potent increase in Tat-mediated HIV-1 production was observed with USP7 in a dose-dependent manner. As expected, deletion of the USP7 gene using the CRISPR-Cas9 method reduced the Tat protein and supported less virus production. Interestingly, the levels of endogenous USP7 increased after HIV-1 infection in human T-cells (MOLT-3) and in mammalian cells transfected with HIV-1 proviral DNA. Thus, HIV-1 Tat is stabilized by the host cell deubiquitinase USP7, leading to enhanced viral production, and HIV-1 in turn up-regulates the USP7 protein level.
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Espert, Lucile, Geneviève Degols, Yea-Lih Lin, Thierry Vincent, Monsef Benkirane, and Nadir Mechti. "Interferon-induced exonuclease ISG20 exhibits an antiviral activity against human immunodeficiency virus type 1." Journal of General Virology 86, no. 8 (August 1, 2005): 2221–29. http://dx.doi.org/10.1099/vir.0.81074-0.
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Interferons (IFNs) encode a family of secreted proteins that provide the front-line defence against viral infections. It was recently shown that ISG20, a new 3′→5′ exoribonuclease member of the DEDD superfamily of exonucleases, represents a novel antiviral pathway in the mechanism of IFN action. In this report, it was shown that ISG20 expression is rapidly and strongly induced during human immunodeficiency virus type 1 (HIV-1) infection. In addition, it was demonstrated that the replication kinetics of an HIV-1-derived virus expressing the ISG20 protein (HIV-1NL4-3ISG20) was delayed in both CEM cells and peripheral blood mononuclear cells. No antiviral effect was observed in cells overexpressing a mutated ISG20 protein defective in exonuclease activity, suggesting that the antiviral effect was due to the exonuclease activity of ISG20. Paradoxically, despite the antiviral activity of ISG20 protein, virus rescue observed in HIV-1NL4-3ISG20-infected cells was not due to mutation or partial deletion of the ISG20 transgene, suggesting that the virus was able to counteract the cellular defences. In addition, HIV-1-induced apoptosis was significantly reduced in HIV-1NL4-3ISG20-infected cells suggesting that emergence of HIV-1NL4-3ISG20 was associated with the inhibition of HIV-1-induced apoptosis. Altogether, these data reflect the ineffectiveness of virus replication in cells overexpressing ISG20 and demonstrate that ISG20 represents a new factor in the IFN-mediated antiviral barrier against HIV-1.
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Agrawal, Lokesh, Qingwen Jin, Jeff Altenburg, L. Meyer, R. Tubiana, Ioannis Theodorou, and Ghalib Alkhatib. "CCR5Δ32 Protein Expression and Stability Are Critical for Resistance to Human Immunodeficiency Virus Type 1 In Vivo." Journal of Virology 81, no. 15 (May 23, 2007): 8041–49. http://dx.doi.org/10.1128/jvi.00068-07.
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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection of individuals carrying the two alleles of the CCR5Δ32 mutation (CCR5−/−) has rarely been reported, but how the virus overcomes the CCR5Δ32 protective effect in these cases has not been delineated. We have investigated this in 6 infected (HIV+) and 25 HIV− CCR5−/− individuals. CD4+ T lymphocytes isolated from HIV− CCR5−/− peripheral blood mononuclear cells (PBMCs) showed lower levels of CXCR4 expression that correlated with lower X4 Env-mediated fusion. Endogenous CCR5Δ32 protein was detected in all HIV− CCR5−/− PBMC samples (n = 25) but not in four of six unrelated HIV+ CCR5−/− PBMC samples. Low levels were detected in another two HIV+ CCR5−/− PBMC samples. The expression of adenovirus 5 (Ad5)-encoded CCR5Δ32 protein restored the protective effect in PBMCs from three HIV+ CCR5−/− individuals but failed to restore the protective effect in PBMCs isolated from another three HIV+ CCR5−/− individuals. In the latter samples, pulse-chase analyses demonstrated the disappearance of endogenous Ad5-encoded CCR5Δ32 protein and the accumulation of Ad5-encoded CCR5 during the chase periods. PBMCs isolated from CCR5−/− individuals showed resistance to primary X4 but were readily infected by a lab-adapted X4 strain. Low levels of Ad5-encoded CCR5Δ32 protein conferred resistance to primary X4 but not to lab-adapted X4 virus. These data provide strong support for the hypothesis that the CCR5Δ32 protein actively confers resistance to HIV-1 in vivo and suggest that the loss or reduction of CCR5Δ32 protein expression may account for HIV-1 infection of CCR5−/− individuals. The results also suggest that other cellular or virally induced factors may be involved in the stability of CCR5Δ32 protein.
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Kotov, Alexander, Jing Zhou, Paula Flicker, and Christopher Aiken. "Association of Nef with the Human Immunodeficiency Virus Type 1 Core." Journal of Virology 73, no. 10 (October 1, 1999): 8824–30. http://dx.doi.org/10.1128/jvi.73.10.8824-8830.1999.
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ABSTRACT Highly conserved among primate lentiviruses, the human immunodeficiency virus type 1 (HIV-1) Nef protein enhances viral infectivity by an unknown mechanism. Nef-defective virions are blocked at a stage of the HIV-1 life cycle between entry and reverse transcription, possibly virus uncoating. Nef is present in purified HIV-1 particles; however, it has not been determined whether Nef is specifically recruited into HIV-1 particles or whether virion-associated Nef plays a functional role in HIV-1 replication. To address the specificity and potential functionality of virion-associated Nef, we determined the subviral localization of Nef. HIV-1 cores were isolated by detergent treatment of concentrated virions followed by equilibrium density gradient sedimentation. Relative to HIV-1 virions, HIV-1 cores contained equivalent amounts of reverse transcriptase and integrase, decreased amounts of the viral matrix protein, and trace quantities of the viral transmembrane glycoprotein gp41. Examination of the particles by electron microscopy revealed cone-shaped structures characteristic of lentiviral cores. Similar quantities of proteolytically processed Nef protein were detected in gradient fractions of HIV-1 cores and intact virions. In addition, detergent-resistant subviral complexes isolated from immature HIV-1 particles contained similar quantities of Nef as untreated virions. These results demonstrate that Nef stably associates with the HIV-1 core and suggest that virion-associated Nef plays a functional role in accelerating HIV-1 replication.
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McGettigan, James P., Satyam Sarma, Jan M. Orenstein, Roger J. Pomerantz, and Matthias J. Schnell. "Expression and Immunogenicity of Human Immunodeficiency Virus Type 1 Gag Expressed by a Replication-Competent Rhabdovirus-Based Vaccine Vector." Journal of Virology 75, no. 18 (September 15, 2001): 8724–32. http://dx.doi.org/10.1128/jvi.75.18.8724-8732.2001.
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ABSTRACT A replication-competent rhabdovirus-based vector expressing human immunodeficiency virus type 1 (HIV-1) Gag protein was characterized on human cell lines and analyzed for the induction of a cellular immune response in mice. We previously described a rabies virus (RV) vaccine strain-based vector expressing HIV-1 gp160. The recombinant RV was able to induce strong humoral and cellular immune responses against the HIV-1 envelope protein in mice (M. J. Schnell et al., Proc. Natl. Acad. Sci. USA 97:3544–3549, 2000; J. P. McGettigan et al., J. Virol. 75:4430–4434, 2001). Recent research suggests that the HIV-1 Gag protein is another important target for cell-mediated host immune defense. Here we show that HIV-1 Gag can efficiently be expressed by RV on both human and nonhuman cell lines. Infection of HeLa cells with recombinant RV expressing HIV-1 Gag resulted in efficient expression of HIV-1 precursor protein p55 as indicated by both immunostaining and Western blotting. Moreover, HIV-1 p24 antigen capture enzyme-linked immunosorbent assay and electron microscopy showed efficient release of HIV-1 virus-like particles in addition to bullet-shaped RV particles in the supernatants of the infected cells. To initially screen the immunogenicity of this new vaccine vector, BALB/c mice received a single vaccination with the recombinant RV expressing HIV-1 Gag. Immunized mice developed a vigorous CD8+ cytotoxic T-lymphocyte response against HIV-1 Gag. In addition, 26.8% of CD8+T cells from mice immunized with RV expressing HIV-1 Gag produced gamma interferon after challenge with a recombinant vaccinia virus expressing HIV-1 Gag. These results further confirm and extend the potency of RV-based vectors as a potential HIV-1 vaccine.
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Gordón-Alonso, Mónica, Vera Rocha-Perugini, Susana Álvarez, Olga Moreno-Gonzalo, Ángeles Ursa, Soraya López-Martín, Nuria Izquierdo-Useros, et al. "The PDZ-adaptor protein syntenin-1 regulates HIV-1 entry." Molecular Biology of the Cell 23, no. 12 (June 15, 2012): 2253–63. http://dx.doi.org/10.1091/mbc.e11-12-1003.
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Syntenin-1 is a cytosolic adaptor protein involved in several cellular processes requiring polarization. Human immunodeficiency virus type 1 (HIV-1) attachment to target CD4+T-cells induces polarization of the viral receptor and coreceptor, CD4/CXCR4, and cellular structures toward the virus contact area, and triggers local actin polymerization and phosphatidylinositol 4,5-bisphosphate (PIP2) production, which are needed for successful HIV infection. We show that syntenin-1 is recruited to the plasma membrane during HIV-1 attachment and associates with CD4, the main HIV-1 receptor. Syntenin-1 overexpression inhibits HIV-1 production and HIV-mediated cell fusion, while syntenin depletion specifically increases HIV-1 entry. Down-regulation of syntenin-1 expression reduces F-actin polymerization in response to HIV-1. Moreover, HIV-induced PIP2accumulation is increased in syntenin-1–depleted cells. Once the virus has entered the target cell, syntenin-1 polarization toward the viral nucleocapsid is lost, suggesting a spatiotemporal regulatory role of syntenin-1 in actin remodeling, PIP2production, and the dynamics of HIV-1 entry.
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Yu, Jae-Sung, James W. Peacock, Stacie Vanleeuwen, Tsungda Hsu, William R. Jacobs, Mark J. Cayabyab, Norman L. Letvin, et al. "Generation of Mucosal Anti-Human Immunodeficiency Virus Type 1 T-Cell Responses by Recombinant Mycobacterium smegmatis▿." Clinical and Vaccine Immunology 13, no. 11 (August 30, 2006): 1204–11. http://dx.doi.org/10.1128/cvi.00195-06.
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ABSTRACT A successful vaccine vector for human immunodeficiency virus type 1 (HIV-1) should induce anti-HIV-1 immune responses at mucosal sites. We have generated recombinant Mycobacterium smegmatis vectors that express the HIV-1 group M consensus envelope protein (Env) as a surface, intracellular, or secreted protein and have tested them in animals for induction of both anti-HIV-1 T-cell and antibody responses. Recombinant M. smegmatis engineered for expression of secreted protein induced optimal T-cell gamma interferon enzyme-linked immunospot assay responses to HIV-1 envelope in the spleen, female reproductive tract, and lungs. Unlike with the induction of T-cell responses, priming and boosting with recombinant M. smegmatis did not induce anti-HIV-1 envelope antibody responses, due primarily to insufficient protein expression of the insert. However, immunization with recombinant M. smegmatis expressing HIV-1 Env was able to prime for an HIV-1 Env protein boost for the induction of anti-HIV-1 antibody responses.
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Sakalian, Michael, Stephanie S. Dittmer, A. Dustin Gandy, Nathan D. Rapp, Aleš Zábranský, and Eric Hunter. "The Mason-Pfizer Monkey Virus Internal Scaffold Domain Enables In Vitro Assembly of Human Immunodeficiency Virus Type 1 Gag." Journal of Virology 76, no. 21 (November 1, 2002): 10811–20. http://dx.doi.org/10.1128/jvi.76.21.10811-10820.2002.
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ABSTRACT The Mason-Pfizer monkey virus (M-PMV) Gag protein possesses the ability to assemble into an immature capsid when synthesized in a reticulocyte lysate translation system. In contrast, the human immunodeficiency virus (HIV) Gag protein is incapable of assembly in parallel assays. To enable the assembly of HIV Gag, we have combined or inserted regions of M-PMV Gag into HIV Gag. By both biochemical and morphological criteria, several of these chimeric Gag molecules are capable of assembly into immature capsid-like structures in this in vitro system. Chimeric species containing large regions of M-PMV Gag fused to HIV Gag sequences failed to assemble, while species consisting of only the M-PMV p12 region, and its internal scaffold domain (ISD), fused to HIV Gag were capable of assembly, albeit at reduced kinetics compared to M-PMV Gag. The ability of the ISD to induce assembly of HIV Gag, which normally assembles at the plasma membrane, suggests a common requirement for a concentrating factor in retrovirus assembly. Despite the dramatic effect of the ISD on chimera assembly, the function of HIV Gag domains in that process was found to remain essential, since an assembly-defective mutant of HIV CA, M185A, abolished assembly when introduced into the chimera. This continued requirement for HIV Gag domain function in the assembly of chimeric molecules will allow this in vitro system to be used for the analysis of potential inhibitors of HIV immature particle assembly.
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Contarino, Mark, Arangassery R. Bastian, Ramalingam Venkat Kalyana Sundaram, Karyn McFadden, Caitlin Duffy, Vamshi Gangupomu, Michelle Baker, Cameron Abrams, and Irwin Chaiken. "Chimeric Cyanovirin-MPER Recombinantly Engineered Proteins Cause Cell-Free Virolysis of HIV-1." Antimicrobial Agents and Chemotherapy 57, no. 10 (July 15, 2013): 4743–50. http://dx.doi.org/10.1128/aac.00309-13.
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ABSTRACTHuman immunodeficiency virus (HIV) is the primary etiologic agent responsible for the AIDS pandemic. In this work, we used a chimeric recombinant protein strategy to test the possibility of irreversibly destroying the HIV-1 virion using an agent that simultaneously binds the Env protein and viral membrane. We constructed a fusion of the lectin cyanovirin-N (CVN) and the gp41 membrane-proximal external region (MPER) peptide with a variable-length (Gly4Ser)xlinker (wherexis 4 or 8) between the C terminus of the former and N terminus of the latter. The His-tagged recombinant proteins, expressed in BL21(DE3)pLysS cells and purified by immobilized metal affinity chromatography followed by gel filtration, were found to display a nanomolar efficacy in blocking BaL-pseudotyped HIV-1 infection of HOS.T4.R5 cells. This antiviral activity was HIV-1 specific, since it did not inhibit cell infection by vesicular stomatitis virus (VSV) or amphotropic-murine leukemia virus. Importantly, the chimeric proteins were found to release intraviral p24 protein from both BaL-pseudotyped HIV-1 and fully infectious BaL HIV-1 in a dose-dependent manner in the absence of host cells. The addition of either MPER or CVN was found to outcompete this virolytic effect, indicating that both components of the chimera are required for virolysis. The finding that engaging the Env protein spike and membrane using a chimeric ligand can destabilize the virus and lead to inactivation opens up a means to investigate virus particle metastability and to evaluate this approach for inactivation at the earliest stages of exposure to virus and before host cell encounter.
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Hatanaka, Hideki, Oleg Iourin, Zihe Rao, Elizabeth Fry, Alan Kingsman, and David I. Stuart. "Structure of Equine Infectious Anemia Virus Matrix Protein." Journal of Virology 76, no. 4 (February 15, 2002): 1876–83. http://dx.doi.org/10.1128/jvi.76.4.1876-1883.2002.
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ABSTRACT The Gag polyprotein is key to the budding of retroviruses from host cells and is cleaved upon virion maturation, the N-terminal membrane-binding domain forming the matrix protein (MA). The 2.8-Å resolution crystal structure of MA of equine infectious anemia virus (EIAV), a lentivirus, reveals that, despite showing no sequence similarity, more than half of the molecule can be superimposed on the MAs of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV). However, unlike the structures formed by HIV-1 and SIV MAs, the oligomerization state observed is not trimeric. We discuss the potential of this molecule for membrane binding in the light of conformational differences between EIAV MA and HIV or SIV MA.
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Soper, Andrew, Guillermo Juarez-Fernandez, Hirofumi Aso, Miyu Moriwaki, Eri Yamada, Yusuke Nakano, Yoshio Koyanagi, and Kei Sato. "Various plus unique: Viral protein U as a plurifunctional protein for HIV-1 replication." Experimental Biology and Medicine 242, no. 8 (February 28, 2017): 850–58. http://dx.doi.org/10.1177/1535370217697384.
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Human immunodeficiency virus type 1 (HIV-1), the causative agent of acquired immunodeficiency syndrome, encodes four accessory genes, one of which is viral protein U (Vpu). Recently, the study of Vpu has been of great interest. For instance, various cellular proteins are degraded (e.g. CD4) and down-modulated (e.g. tetherin) by Vpu. Vpu also antagonizes the function of tetherin and inhibits NF-κB. Moreover, Vpu is a viroporin forming ion channels and may represent a promising target for anti-HIV-1 drugs. In this review, we summarize the domains/residues that are responsible for Vpu’s functions, describe the current understanding of the role of Vpu in HIV-1-infected cells, and review the effect of Vpu on HIV-1 in replication and pathogenesis. Future investigations that simultaneously assess a combination of Vpu functions are required to clearly delineate the most important functions for viral replication. Impact statement Viral protein U (Vpu) is a unique protein encoded by human immunodeficiency virus type 1 (HIV-1) and related lentiviruses, playing multiple roles in viral replication and pathogenesis. In this review, we briefly summarize the most up-to-date knowledge of HIV-1 Vpu.
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Tuffy, Kevin M., Rebecca J. Kaddis Maldonado, Jordan Chang, Paul Rosenfeld, Alan Cochrane, and Leslie J. Parent. "HIV-1 Gag Forms Ribonucleoprotein Complexes with Unspliced Viral RNA at Transcription Sites." Viruses 12, no. 11 (November 9, 2020): 1281. http://dx.doi.org/10.3390/v12111281.
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The ability of the retroviral Gag protein of Rous sarcoma virus (RSV) to transiently traffic through the nucleus is well-established and has been implicated in genomic RNA (gRNA) packaging Although other retroviral Gag proteins (human immunodeficiency virus type 1, HIV-1; feline immunodeficiency virus, FIV; Mason-Pfizer monkey virus, MPMV; mouse mammary tumor virus, MMTV; murine leukemia virus, MLV; and prototype foamy virus, PFV) have also been observed in the nucleus, little is known about what, if any, role nuclear trafficking plays in those viruses. In the case of HIV-1, the Gag protein interacts in nucleoli with the regulatory protein Rev, which facilitates nuclear export of gRNA. Based on the knowledge that RSV Gag forms viral ribonucleoprotein (RNPs) complexes with unspliced viral RNA (USvRNA) in the nucleus, we hypothesized that the interaction of HIV-1 Gag with Rev could be mediated through vRNA to form HIV-1 RNPs. Using inducible HIV-1 proviral constructs, we visualized HIV-1 Gag and USvRNA in discrete foci in the nuclei of HeLa cells by confocal microscopy. Two-dimensional co-localization and RNA-immunoprecipitation of fractionated cells revealed that interaction of nuclear HIV-1 Gag with USvRNA was specific. Interestingly, treatment of cells with transcription inhibitors reduced the number of HIV-1 Gag and USvRNA nuclear foci, yet resulted in an increase in the degree of Gag co-localization with USvRNA, suggesting that Gag accumulates on newly synthesized viral transcripts. Three-dimensional imaging analysis revealed that HIV-1 Gag localized to the perichromatin space and associated with USvRNA and Rev in a tripartite RNP complex. To examine a more biologically relevant cell, latently infected CD4+ T cells were treated with prostratin to stimulate NF-κB mediated transcription, demonstrating striking localization of full-length Gag at HIV-1 transcriptional burst site, which was labelled with USvRNA-specific riboprobes. In addition, smaller HIV-1 RNPs were observed in the nuclei of these cells. These data suggest that HIV-1 Gag binds to unspliced viral transcripts produced at the proviral integration site, forming vRNPs in the nucleus.
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Komano, Jun, Kosuke Miyauchi, Zene Matsuda, and Naoki Yamamoto. "Inhibiting the Arp2/3 Complex Limits Infection of Both Intracellular Mature Vaccinia Virus and Primate Lentiviruses." Molecular Biology of the Cell 15, no. 12 (December 2004): 5197–207. http://dx.doi.org/10.1091/mbc.e04-04-0279.
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Characterizing cellular factors involved in the life cycle of human immunodeficiency virus type 1 (HIV-1) is an initial step toward controlling replication of HIV-1. Actin polymerization mediated by the Arp2/3 complex has been found to play a critical role in some pathogens' intracellular motility. We have asked whether this complex also contributes to the viral life cycles including that of HIV-1. We have used both the acidic domains from actin-related protein (Arp) 2/3 complex-binding proteins such as the Wiscott-Aldrich syndrome protein (N-WASP) or cortactin, and siRNA directing toward Arp2 to inhibit viral infection. HIV-1, simian immunodeficiency virus (SIV), and intracellular mature vaccinia virus (IMV) were sensitive to inhibition of the Arp2/3 complex, whereas MLV, HSV-1, and adenovirus were not. Interestingly, pseudotyping HIV-1 with vesicular stomatitis virus G protein (VSV-G) overcame this inhibition. Constitutive inhibition of the Arp2/3 complex in the T-cell line H9 also blocked replication of HIV-1. These data suggested the existence of an Arp2/3 complex-dependent event during the early phase of the life cycles of both primate lentiviruses and IMV. Inhibiting the HIV-1's ability to activate Arp2/3 complex could be a potential chemotherapeutic intervention for acquired immunodeficiency syndrome (AIDS).
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Gurer, Cagan, Lionel Berthoux, and Jeremy Luban. "Covalent Modification of Human Immunodeficiency Virus Type 1 p6 by SUMO-1." Journal of Virology 79, no. 2 (January 15, 2005): 910–17. http://dx.doi.org/10.1128/jvi.79.2.910-917.2005.
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ABSTRACT The p6 domain of the human immunodeficiency virus type 1 (HIV-1) Gag polyprotein mediates virion budding from infected cells via protein-protein contacts with the class E vacuolar protein sorting factors, Tsg101 and AIP1/ALIX. Interaction with Tsg101 is strengthened by covalent attachment of monovalent ubiquitin to HIV-1 p6. To identify additional host factors that bind to HIV-1 p6, a human cDNA library was screened in the yeast two-hybrid system. HIV-1 p6 was found to interact with small ubiquitin-like modifier 1 (SUMO-1) as well as the E2 SUMO-1 transfer enzyme, Ubc9. Interaction with p6 was also detected with Daxx, a cellular protein to which SUMO-1 is sometimes covalently attached. SUMO-1 was incorporated into HIV-1 virions where it was protected within the virion membrane from digestion by exogenous protease. Of the two lysine residues in p6, lysine 27 uniquely served as a site of covalent SUMO-1 attachment. As previously reported, though, HIV-1 bearing the p6-K27R mutation replicated just like the wild type. Overproduction of SUMO-1 in HIV-1 producer cells had no apparent effect on virion release or on virion protein or RNA content. Infectivity of the resulting virions, though, was decreased, with the defect occurring after membrane fusion, at the time of viral cDNA synthesis. HIV-1 bearing the p6-K27R mutation was insensitive to SUMO-1 overexpression, suggesting that covalent attachment of SUMO-1 to p6 is detrimental to HIV-1 replication.
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Wong, G. H., J. F. Krowka, D. P. Stites, and D. V. Goeddel. "In vitro anti-human immunodeficiency virus activities of tumor necrosis factor-alpha and interferon-gamma." Journal of Immunology 140, no. 1 (January 1, 1988): 120–24. http://dx.doi.org/10.4049/jimmunol.140.1.120.
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Abstract Treatment of cells with tumor necrosis factor-alpha and interferon-gamma greatly reduces their susceptibility to infection with human immunodeficiency virus and suppresses the production of human immunodeficiency virus (HIV) mRNA, core protein p24, and infectious HIV. The combination treatment is cytotoxic for HIV-infected cells and reduces HIV RNA levels in chronically infected cells.
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McGettigan, James P., Heather D. Foley, Igor M. Belyakov, Jay A. Berzofsky, Roger J. Pomerantz, and Matthias J. Schnell. "Rabies Virus-Based Vectors Expressing Human Immunodeficiency Virus Type 1 (HIV-1) Envelope Protein Induce a Strong, Cross-Reactive Cytotoxic T-Lymphocyte Response against Envelope Proteins from Different HIV-1 Isolates." Journal of Virology 75, no. 9 (May 1, 2001): 4430–34. http://dx.doi.org/10.1128/jvi.75.9.4430-4434.2001.
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ABSTRACT Novel viral vectors that are able to induce both strong and long-lasting immune responses may be required as effective vaccines for human immunodeficiency virus type 1 (HIV-1) infection. Our previous experiments with a replication-competent vaccine strain-based rabies virus (RV) expressing HIV-1 envelope protein from a laboratory-adapted HIV-1 strain (NL4–3) and a primary HIV-1 isolate (89.6) showed that RV-based vectors are excellent for B-cell priming. Here we report that cytotoxic T-lymphocyte (CTL) responses against HIV-1 gp160 are induced by recombinant RVs. Our results indicated that a single inoculation of mice with an RV expressing HIV-1 gp160 induced a solid and long-lasting memory CTL response specific for HIV-1 envelope protein. Moreover, CTLs from immunized mice were not restricted to the homologous HIV-1 envelope protein and were able to cross-kill target cells expressing HIV-1 gp160 from heterologous HIV-1 strains. These studies further suggest promise for RV-based vectors to elicit a persistent immune response against HIV-1 and their potential utility as efficacious anti-HIV-1 vaccines.
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Zhou, Yongdong, Liwei Rong, Jennifer Lu, Qinghua Pan, and Chen Liang. "Insulin-Like Growth Factor II mRNA Binding Protein 1 Associates with Gag Protein of Human Immunodeficiency Virus Type 1, and Its Overexpression Affects Virus Assembly." Journal of Virology 82, no. 12 (April 2, 2008): 5683–92. http://dx.doi.org/10.1128/jvi.00189-08.
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ABSTRACT The assembly of human immunodeficiency virus type 1 (HIV-1) particles is driven by viral Gag protein. This function of Gag not only benefits from its self-multimerization property but also depends on its interaction with a number of cellular factors such as TSG101 and ALIX/AIP1 that promote virus budding and release from cell surfaces. However, interaction with Gag also allows some cellular factors such as APOBEC3G and Trim5α to access viral replication machinery and block viral replication. In this study, we report a new HIV-1 Gag-binding factor named insulin-like growth factor II mRNA binding protein 1 (IMP1). Gag-IMP1 interaction requires the second zinc finger of the nucleocapsid (NC) domain of Gag and the KH3 and KH4 domains of IMP1. A fourfold reduction of HIV-1 infectivity was seen with overexpression of the wild-type IMP1 and its mutant that is able to interact with Gag but not with overexpression of IMP1 mutants exhibiting Gag-binding deficiency. The decreased viral infectivity was further shown as a result of diminished viral RNA packaging, abrogated Gag processing on the cellular membranes, and impeded maturation of virus particles. Together, these results demonstrate that IMP1 interacts with HIV-1 Gag protein and is able to block the formation of infectious HIV-1 particles.
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Ojo-Amaize, E. A., P. Nishanian, D. E. Keith, R. L. Houghton, D. F. Heitjan, J. L. Fahey, and J. V. Giorgi. "Antibodies to human immunodeficiency virus in human sera induce cell-mediated lysis of human immunodeficiency virus-infected cells." Journal of Immunology 139, no. 7 (October 1, 1987): 2458–63. http://dx.doi.org/10.4049/jimmunol.139.7.2458.
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Abstract The capacity of human immunodeficiency virus (HIV) antibody-positive sera from homosexually active men without acquired immune deficiency syndrome to lyse the HIV-infected T cell lines MOLT-4f and CCRF-CEM (CEM) in cooperation with lymphocytes from normal donors was investigated. Twenty-seven HIV antibody-positive sera, most of which enhanced the killing of HIV-infected MOLT-4f and CEM target cells by normal mononuclear cells were studied in detail. HIV antibody-positive sera resulted in lysis at dilutions as high as 1/10,000. HIV antibody-negative sera did not augment lysis of infected target cells. In addition, lysis of uninfected targets was not enhanced in the presence of HIV antibody-positive sera. Because fractionation of the HIV antibody-positive sera on a protein A affinity column resulted in recovery of the activity from the IgG fraction, the extra cytotoxic activity mediated by nonimmune cells in the presence of immune sera appears to be antibody-dependent. Furthermore, the cytotoxic effector cells were in the nonrosetting fraction of lymphocytes and expressed Leu-11 (cluster designation (CD)15) antigens, which is characteristic of cells participating in antibody-dependent cellular cytotoxicity reactions. The antibody specificity of the sera, determined by radioimmunoprecipitation, provides evidence that antibody-dependent cellular cytotoxicity can occur even when there are no detectable antibodies directed against gag proteins. Sera which lacked detectable antibodies to the envelope protein gp120 by radioimmunoprecipitation did not mediate antibody-dependent cellular cytotoxicity.
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Clerzius, Guerline, Jean-François Gélinas, Aïcha Daher, Marion Bonnet, Eliane F. Meurs, and Anne Gatignol. "ADAR1 Interacts with PKR during Human Immunodeficiency Virus Infection of Lymphocytes and Contributes to Viral Replication." Journal of Virology 83, no. 19 (July 15, 2009): 10119–28. http://dx.doi.org/10.1128/jvi.02457-08.
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ABSTRACT The interferon-induced protein kinase RNA activated (PKR) is activated after virus infection. This activation is transient during the human immunodeficiency virus type 1 (HIV-1) infection of lymphocytes, and the protein is not activated at the peak of infection. We observed that interferon-induced adenosine deaminase acting on RNA 1-p150 (ADAR1-p150) and ADAR1-p110 expression increases while the virus replicates actively. Furthermore, both forms of ADAR1 show enhanced interactions with PKR at the peak of HIV infection, suggesting a role for this protein in the regulation of PKR activation. We observed that ADAR1-p150, as previously shown for the TAR RNA binding protein (TRBP), reverses the PKR inhibition of HIV expression and production in HEK 293T cells. This activity requires the Z-DNA binding motif and the three double-stranded RNA binding domains but not the catalytic domain. In astrocytic cells, ADAR1-p150 increased HIV expression and production to an extent similar to that of TRBP. Small interfering RNAs against ADAR1-p150 moderately decreased HIV production. These results indicate that two interferon-induced proteins, ADAR1 and PKR, have antagonistic functions on HIV production. They suggest that ADAR1 and TRBP belong to a multiprotein complex that inhibits PKR during the HIV infection of lymphocytes.
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Krishnan, Lavanya, Kenneth A. Matreyek, Ilker Oztop, Kyeongeun Lee, Christopher H. Tipper, Xiang Li, Mohd J. Dar, Vineet N. KewalRamani, and Alan Engelman. "The Requirement for Cellular Transportin 3 (TNPO3 or TRN-SR2) during Infection Maps to Human Immunodeficiency Virus Type 1 Capsid and Not Integrase." Journal of Virology 84, no. 1 (October 21, 2009): 397–406. http://dx.doi.org/10.1128/jvi.01899-09.
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ABSTRACT Recent genome-wide screens have highlighted an important role for transportin 3 in human immunodeficiency virus type 1 (HIV-1) infection and preintegration complex (PIC) nuclear import. Moreover, HIV-1 integrase interacted with recombinant transportin 3 protein under conditions whereby Moloney murine leukemia virus (MLV) integrase failed to do so, suggesting that integrase-transportin 3 interactions might underscore active retroviral PIC nuclear import. Here we correlate infectivity defects in transportin 3 knockdown cells with in vitro protein binding affinities for an expanded set of retroviruses that include simian immunodeficiency virus (SIV), bovine immunodeficiency virus (BIV), equine infectious anemia virus (EIAV), feline immunodeficiency virus (FIV), and Rous sarcoma virus (RSV) to critically address the role of integrase-transportin 3 interactions in viral infection. Lentiviruses, with the exception of FIV, display a requirement for transportin 3 in comparison to MLV and RSV, yielding an infection-based dependency ranking of SIV > HIV-1 > BIV and EIAV > MLV, RSV, and FIV. In vitro pulldown and surface plasmon resonance assays, in contrast, define a notably different integrase-transportin 3 binding hierarchy: FIV, HIV-1, and BIV > SIV and MLV > EIAV. Our results therefore fail to support a critical role for integrase binding in dictating transportin 3 dependency during retrovirus infection. In addition to integrase, capsid has been highlighted as a retroviral nuclear import determinant. Accordingly, MLV/HIV-1 chimera viruses pinpoint the genetic determinant of sensitization to transportin 3 knockdown to the HIV-1 capsid protein. We therefore conclude that capsid, not integrase, is the dominant viral factor that dictates transportin 3 dependency during HIV-1 infection.
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Pontzer, C. H., J. K. Yamamoto, F. W. Bazer, T. L. Ott, and H. M. Johnson. "Potent anti-feline immunodeficiency virus and anti-human immunodeficiency virus effect of IFN-tau." Journal of Immunology 158, no. 9 (May 1, 1997): 4351–57. http://dx.doi.org/10.4049/jimmunol.158.9.4351.
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Abstract Ovine IFN-tau is a newly described protein related to IFN-alpha that is responsible for maternal recognition of pregnancy in sheep. It has been shown to exhibit potent antiviral and antiproliferative activity. To determine its antiviral activity against feline immunodeficiency virus (FIV) and HIV, the activity of the RNA-dependent DNA polymerase, reverse transcriptase, was assayed in FIV- and HIV-infected feline and human PBL treated with IFN-tau. Significant dose-dependent inhibition of reverse transcriptase activity by IFN-tau was detected by day 6 of culture and was maintained through the peak of virus replication. In addition, production of the FIV core protein, p25, was blocked by IFN-tau. Both the amino- and carboxyl-terminal regions of IFN-tau, as identified by synthetic peptides, appear to be involved in its antiretroviral activity. Comparison of the anti-HIV activities of IFN-tau and recombinant human IFN-alpha2 (rHuIFN-alpha2) indicated that while rHuIFN-alpha2 was toxic to cells at 10,000 U/ml, IFN-tau antiretroviral activity was not associated with a decrease in either cell viability or immunologic reactivity. Thus, IFN-tau displayed potent anti-FIV and anti-HIV activity without the cytotoxicity associated with high concentrations of rHuIFN-alpha2.
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Bennett, Erin M., Andrew M. L. Lever, and Jane F. Allen. "Human Immunodeficiency Virus Type 2 Gag Interacts Specifically with PRP4, a Serine-Threonine Kinase, and Inhibits Phosphorylation of Splicing Factor SF2." Journal of Virology 78, no. 20 (October 15, 2004): 11303–12. http://dx.doi.org/10.1128/jvi.78.20.11303-11312.2004.
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ABSTRACT Using a yeast two-hybrid screen of a T-cell cDNA library to identify cellular proteins that bind to the human immunodeficiency virus type 2 (HIV-2) Gag polyprotein, we identified PRP4, a serine-threonine protein kinase. Specific interaction of PRP4 and HIV-2 Gag was confirmed in in vitro and in vivo assays. The interacting region of HIV-2 Gag is located in the conserved matrix and capsid domains, while both the RS (arginine-serine-rich) domain and the KS (kinase) domain of PRP4 are able to bind to HIV-2 Gag. PRP4 is not incorporated into virus particles. HIV-2 Gag is able to inhibit PRP4-mediated phosphorylation of the splicing factor SF2. This is also observed with Gag from simian immunodeficiency virus, a closely related virus, but not with Gag from human T-cell lymphotropic virus type 1. Our results provide evidence for a novel interaction between Gag and a cellular protein kinase involved in the control of constitutive splicing in two closely related retroviruses. We hypothesize that as Gag accumulates in the cell, down regulation of splicing occurs through reduced phosphorylation of SF2. At late stages of infection, this interaction may replace the function of the early viral regulatory protein Rev.
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Parveen, Zahida, Muhammad Mukhtar, Adrienne Goodrich, Edward Acheampong, Ralph Dornburg, and Roger J. Pomerantz. "Cross-Packaging of Human Immunodeficiency Virus Type 1 Vector RNA by Spleen Necrosis Virus Proteins: Construction of a New Generation of Spleen Necrosis Virus-Derived Retroviral Vectors." Journal of Virology 78, no. 12 (June 15, 2004): 6480–88. http://dx.doi.org/10.1128/jvi.78.12.6480-6488.2004.
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ABSTRACT The ability of the nonlentiviral retrovirus spleen necrosis virus (SNV) to cross-package the genomic RNA of the distantly related human immunodeficiency virus type 1 (HIV-1) and vice versa was analyzed. Such a model may allow us to further study HIV-1 replication and pathogenesis, as well as to develop safe gene therapy vectors. Our results suggest that SNV can cross-package HIV-1 genomic RNA but with lower efficiency than HIV-1 proteins. However, HIV-1-specific proteins were unable to cross-package SNV RNA. We also constructed SNV-based gag-pol chimeric variants by replacing the SNV integrase with the HIV-1 integrase, based on multiple sequence alignments and domain analyses. These analyses revealed that there are conserved domains in all retroviral integrase open reading frames (orf), despite the divergence in the primary sequences. The transcomplementation assays suggested that SNV proteins recognized one of the chimeric variants. This demonstrated that HIV-1 integrase is functional in the SNV gag-pol orf with a lower transduction efficiency, utilizing homologous (SNV) RNA, as well as the heterologous vector RNA of HIV-1. These findings suggest that homology in the conserved sequences of the integrase protein may not be fully competent in the replacement of protein(s) from one retrovirus to another, and there are likely several other factors involved in each of the steps related to replication, integration, and infection. However, further studies to dissect the gag-pol region will be critical for understanding the mechanisms involved in the cleavage of reverse transcriptase, RNase H, and integrase. These studies should provide further insight into the design and development of novel molecular approaches to block HIV-1 replication and to construct a new generation of SNV-based vectors.