Aberrant Gag protein composition of a human immunodeficiency virus type 1 vif mutant produced in primary lymphocytes

Simm, Malgorzata; Shahabuddin, M.; Chao, Wei; Allan, Jonathan S.; Volsky, David J.

doi:10.1128/jvi.69.7.4582-4586.1995

Cited by 105 publications

(64 citation statements)

References 34 publications

(102 reference statements)

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“…5 and 6) and previous studies suggest that Vif does not affect viral RNA encapsidation (3,40), dimerization, or the stability of the RNA dimer linkage. Altered Gag processing has been demonstrated in vif mutant virions (3,34), raising the possibility that Vif might affect the NC protein, p24 Gag, or the spatial organization of Gag proteins within the nucleoprotein complex and thereby influence reverse transcription. For example, an effect on the NC protein might affect reverse transcription, since in vitro studies have shown that the NC protein decreases the probability of termination of reverse transcription at certain pause sites, enhances strand transfers, promotes selective DNA annealing, and accelerates the renaturation of complementary DNA sequences (20,25,39).…”

Section: Discussionmentioning

confidence: 99%

Role of Vif in human immunodeficiency virus type 1 reverse transcription

Goncalves

Korin

Zack

et al. 1996

J Virol

110

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The Vif protein of human immunodeficiency virus type 1 (HIV-1) is important for virion infectivity. Previous studies have shown that vif mutant HIV-1 virions are defective in their ability to synthesize proviral DNA in vivo. Here, we examine the role of Vif in viral DNA synthesis in the endogenous reverse transcriptase (RT) reaction, an in vitro assay in which virions synthesize viral DNA by using endogenous viral RNA as a template. vif mutant virions showed a significant reduction in endogenous RT activity despite similar levels of exogenous RT activity. Analysis of the viral DNA products on agarose gels demonstrated that this reflects reduced synthesis of short minus-and plus-strand DNA products in addition to those of full genomic length. Quantitative PCR analysis of endogenous reverse transcription provided further evidence for reduced formation of both initial and completed reverse transcripts. Vif had no effect on genomic RNA dimerization or the stability of the RNA dimer linkage. These results suggest that Vif is important for an early event after virus entry but preceding or during the early stages of viral DNA synthesis. This may be due to an intrinsic effect on reverse transcription or a preceding postentry event(s), such as virion uncoating or disassembly of the virion core. Drugs targeted to Vif function may provide a new therapeutic approach to inhibiting HIV-1 reverse transcription.

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Section: Discussionmentioning

confidence: 99%

Role of Vif in human immunodeficiency virus type 1 reverse transcription

Goncalves

Korin

Zack

et al. 1996

J Virol

110

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“…Editing patterns are dominated by GG-to-AG hypermutations, leading to a high frequency of amino acid substitutions and to the introduction of premature STOP codons (Vartanian et al, 1991). These crippled proviruses express aberrant (misfolded/truncated) viral proteins and are unable to produce infectious particles (Simm et al, 1995).…”

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confidence: 99%

The antiviral factor APOBEC3G improves CTL recognition of cultured HIV-infected T cells

Casartelli

Guivel‐Benhassine

Bouziat

et al. 2009

Journal of Experimental Medicine

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The cytidine deaminase APOBEC3G (A3G) enzyme exerts an intrinsic anti–human immunodeficiency virus (HIV) defense by introducing lethal G-to-A hypermutations in the viral genome. The HIV-1 viral infectivity factor (Vif) protein triggers degradation of A3G and counteracts this antiviral effect. The impact of A3G on the adaptive cellular immune response has not been characterized. We examined whether A3G-edited defective viruses, which are known to express truncated or misfolded viral proteins, activate HIV-1–specific (HS) CD8+ cytotoxic T lymphocytes (CTLs). To this end, we compared the immunogenicity of cells infected with wild-type or Vif-deleted viruses in the presence or absence of the cytidine deaminase. The inhibitory effect of A3G on HIV replication was associated with a strong activation of cocultivated HS-CTLs. CTL activation was particularly marked with Vif-deleted HIV and with viruses harboring A3G. Enzymatically inactive A3G mutants failed to enhance CTL activation. We also engineered proviruses bearing premature stop codons in their genome as scars of A3G editing. These viruses were not infectious but potently activated HS-CTLs. Therefore, the pool of defective viruses generated by A3G represents an underestimated source of viral antigens. Our results reveal a novel function for A3G, acting not only as an intrinsic antiviral factor but also as an inducer of the adaptive immune system.

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“…Mouse monoclonal antibody (mAb) to EWI-2 (8A12) was a kind gift from Dr. Eric Rubinstein (22). Mouse mAb to HIV-1 p24 (AG3.0) was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH, from Dr. Jonathan Allan (40…”

Section: Antibodiesmentioning

confidence: 99%

EWI-2 Inhibits Cell-Cell Fusion at the Virological Presynapse

Whitaker

Symeonides

Munson

et al. 2018

Preprint

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Cell-to-cell transfer of viral particles through the virological synapse (VS) is a highly efficient mode of HIV-1 transmission. Formation of the VS, a transient multiform adhesion structure, is mediated through an interaction between the HIV-1 envelope glycoprotein (Env) and the viral receptor CD4 on the surface of infected cell and target cell, respectively. Given that Env, unlike many other viral fusogens, can mediate the merger of membranes at neutral pH, the close encounter of infected and uninfected cells would seem prone to result in cell-cell fusion and thus the formation of syncytia. However, while it is being recognized now that small, T cell-based syncytia are indeed a defining feature of the natural history of HIV-1, the majority of VSs nevertheless resolve without fusion, thus securing continued virus spread. Gag, the main viral structural component, is partially responsible for restraining Env and preventing it from becoming fusogenic before being incorporated into particles. In addition, a few cellular factors, including tetraspanins and ezrin, have also been shown to inhibit Env's activity while this fusogen is still part of the producer cell.Here, we identify EWI-2, a protein that was previously shown to associate with the tetraspanins CD9 and CD81 and also with ezrin, as a host factor that contributes to the inhibition of Envmediated cell-cell fusion. Using fluorescence microscopy, flow cytometry, and TZM-bl fusion assays, we show that EWI-2, comparable to tetraspanins, while overall being downregulated upon HIV-1 infection, accumulates at the virological presynapse, thus supporting the fusionpreventing activities of the other viral and cellular components.

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Aberrant Gag protein composition of a human immunodeficiency virus type 1 vif mutant produced in primary lymphocytes

Cited by 105 publications

References 34 publications

Role of Vif in human immunodeficiency virus type 1 reverse transcription

Role of Vif in human immunodeficiency virus type 1 reverse transcription

The antiviral factor APOBEC3G improves CTL recognition of cultured HIV-infected T cells

EWI-2 Inhibits Cell-Cell Fusion at the Virological Presynapse

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