Vif is an auxiliary factor of the HIV-1 reverse transcriptase and facilitates abasic site bypass

Cancio, Reynel; Spadari, Silvio; Maga, Giovanni

doi:10.1042/bj20040914

Cited by 21 publications

(30 citation statements)

References 29 publications

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“…Among those, the A3G-binding viral proteins Vif, NC, and IN have all been shown to interact with RT and promote the efficiency of reverse transcription to various levels (11,22,23,29,33). Thus, an unanswered question is whether A3G-mediated inhibition of reverse transcription could be due to the disrupting effect of their associations with RT.…”

Section: Discussionmentioning

confidence: 99%

The Cellular Antiviral Protein APOBEC3G Interacts with HIV-1 Reverse Transcriptase and Inhibits Its Function during Viral Replication

Wang

Chen

et al. 2012

J Virol

101

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cThe cytidine deaminase APOBEC3G (A3G) exerts a multifaceted antiviral effect against HIV-1 infection. First, A3G was shown to be able to terminate HIV infection by deaminating the cytosine residues to uracil in the minus strand of the viral DNA during reverse transcription. Also, a number of studies have indicated that A3G inhibits HIV-1 reverse transcription by a non-editingmediated mechanism. However, the mechanism by which A3G directly disrupts HIV-1 reverse transcription is not fully understood. In the present study, by using a cell-based coimmunoprecipitation (Co-IP) assay, we detected the direct interaction between A3G and HIV-1 reverse transcriptase (RT) in produced viruses and in the cotransfected cells. The data also suggested that their interaction did not require viral genomic RNA bridging or other viral proteins. Additionally, a deletion analysis showed that the RT-binding region in A3G was located between amino acids 65 and 132. Overexpression of the RT-binding polypeptide A3G 65-132 was able to disrupt the interaction between wild-type A3G and RT, which consequently attenuated the anti-HIV effect of A3G on reverse transcription. Overall, this paper provides evidence for the physical and functional interaction between A3G and HIV-1 RT and demonstrates that this interaction plays an important role in the action of A3G against HIV-1 reverse transcription. Several host proteins have been identified as intrinsic restriction factors because of their ability to inhibit HIV replication and/or dissemination (2, 31, 41, 52). Among them, the apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G; here referred to as A3G) is the one that restricts HIV-1 replication through more than one mechanism (17,32,37,38,40). In the absence of the HIV-1 viral infectivity factor (Vif), A3G is incorporated into progeny viruses through its interaction with the nucleocapsid (NC) domain of the Gag protein and/or viral RNA (1,15,56,63). Once these progeny viruses initiate new infection, the incorporated A3G will deaminate the cytidine to uridine in the viral minus-strand DNA during reverse transcription, resulting in hypermutation in the provirus. As a result, the HIV-1 proviral DNA will be no longer functional or degrade rapidly (21,32,38,64). Additionally, the mutated proviral DNA may produce defective or truncated viral polypeptides that represent a significant source of major histocompatibility complex class I (MHC-I)-restricted epitopes to activate HIV-1-specific CD8 ϩ cytotoxic T lymphocytes (CTLs) (12).Reverse transcription catalyzed by HIV-1 reverse transcriptase (RT) is a critical step for HIV-1 to establish its replication cycle. In infected cells, RT employs tRNA 3Lys and the polypurine tract as primers and converts the viral genomic RNA into doublestranded viral DNA (23). This process is catalyzed by both the DNA polymerase and RNase H activities of RT (23,49). Interestingly, in addition to the deaminase activity, A3G has also been shown to directly inhibit HIV-1 reverse transcription by a non...

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Section: Discussionmentioning

confidence: 99%

The Cellular Antiviral Protein APOBEC3G Interacts with HIV-1 Reverse Transcriptase and Inhibits Its Function during Viral Replication

Wang

Chen

et al. 2012

J Virol

101

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“…However, the complex intracellular trafficking and regulation of expression of Vif (65,235,240) as well as its uncharacterized effects on the cytoskeleton and the cell cycle (116,194,236) suggest that its functions are more diverse than previously thought. Consistently, properties of Vif linked to viral assembly and the increasing number of results reporting that hA3G degradation or virion exclusion is not a universal mechanism of viral resistance (114,115,196,221,228) strongly suggest that Vif functions against hA3G and hA3F may involve a modulation of HIV-1 assembly by interacting with RNA or protein components of the viral core (3, 11,23,28,89,104,118,119,212,261). It is widely recognized that HIV-1 virions incorporate a small quantity of the Vif protein (37,68,215), but its precise function in RNP assembly or in reverse transcription remains to be demonstrated.…”

Section: Discussionmentioning

confidence: 69%

“…In keeping with this interpretation, the same group showed that Vif is an integral component of the reverse transcription complexes (30,31). An in vitro study showed that Vif may behave as a cofactor of HIV-1 reverse transcriptase by enhancing its association with nucleic acids, stimulating polymerase activity and facilitating the bypass of abasic sites (28). However, it is paradoxical that the C-terminal region that was required for the stimulation of the polymerization activity is cleaved in virion-associated Vif (119) (see below).…”

Section: Reverse Transcription Defects In Hiv-1 ⌬Vif Virionsmentioning

confidence: 99%

Tumultuous Relationship between the Human Immunodeficiency Virus Type 1 Viral Infectivity Factor (Vif) and the Human APOBEC-3G and APOBEC-3F Restriction Factors

Henriet

Mercenne

Bernacchi

et al. 2009

Microbiol Mol Biol Rev

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SUMMARY The viral infectivity factor (Vif) is dispensable for human immunodeficiency virus type 1 (HIV-1) replication in so-called permissive cells but is required for replication in nonpermissive cell lines and for pathogenesis. Virions produced in the absence of Vif have an aberrant morphology and an unstable core and are unable to complete reverse transcription. Recent studies demonstrated that human APOBEC-3G (hA3G) and APOBEC-3F (hA3F), which are selectively expressed in nonpermissive cells, possess strong anti-HIV-1 activity and are sufficient to confer a nonpermissive phenotype. Vif induces the degradation of hA3G and hA3F, suggesting that its main function is to counteract these cellular factors. Most studies focused on the hypermutation induced by the cytidine deaminase activity of hA3G and hA3F and on their Vif-induced degradation by the proteasome. However, recent studies suggested that several mechanisms are involved both in the antiviral activity of hA3G and hA3F and in the way Vif counteracts these antiviral factors. Attempts to reconcile the studies involving Vif in virus assembly and stability with these recent findings suggest that hA3G and hA3F partially exert their antiviral activity independently of their catalytic activity by destabilizing the viral core and the reverse transcription complex, possibly by interfering with the assembly and/or maturation of the viral particles. Vif could then counteract hA3G and hA3F by excluding them from the viral assembly intermediates through competition for the viral genomic RNA, by regulating the proteolytic processing of Pr55Gag, by enhancing the efficiency of the reverse transcription process, and by inhibiting the enzymatic activities of hA3G and hA3F.

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“…Vif also stabilizes viral nucleoprotein complex through direct interaction with 5' region of HIV-1 genomic RNA [88][89][90][91]. Moreover, Vif modulates viral reverse transcriptase through its C-terminal domain either by stimulating the binding of RT and primer or increasing the polymerization rate of RT [92].…”

Section: Virus Infectivity Factor (Vif)mentioning

confidence: 99%

Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions

Pauza

et al. 2005

Cell Res

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Active host-pathogen interactions take place during infection of human immunodeficiency virus type 1 (HIV-1). Outcomes of these interactions determine the efficiency of viral infection and subsequent disease progression. HIVinfected cells respond to viral invasion with various defensive strategies such as innate, cellular and humoral immune antiviral mechanisms. On the other hand, the virus has also developed various offensive tactics to suppress these host cellular responses. Among many of the viral offensive strategies, HIV-1 viral auxiliary proteins (Tat, Rev, Nef, Vif, Vpr and Vpu) play important roles in the host-pathogen interaction and thus have significant impacts on the outcome of HIV infection. One of the best examples is the interaction of Vif with a host cytidine deaminase APOBEC3G. Although specific roles of other auxiliary proteins are not as well described as Vif-APOBEC3G interaction, it is the goal of this brief review to summarize some of the preliminary findings with the hope to stimulate further discussion and investigation in this exhilarating area of research.

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Vif is an auxiliary factor of the HIV-1 reverse transcriptase and facilitates abasic site bypass

Cited by 21 publications

References 29 publications

The Cellular Antiviral Protein APOBEC3G Interacts with HIV-1 Reverse Transcriptase and Inhibits Its Function during Viral Replication

The Cellular Antiviral Protein APOBEC3G Interacts with HIV-1 Reverse Transcriptase and Inhibits Its Function during Viral Replication

Tumultuous Relationship between the Human Immunodeficiency Virus Type 1 Viral Infectivity Factor (Vif) and the Human APOBEC-3G and APOBEC-3F Restriction Factors

Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions

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