Identification of Two Distinct Human Immunodeficiency Virus Type 1 Vif Determinants Critical for Interactions with Human APOBEC3G and APOBEC3F

Russell, Rebecca A.; Pathak, Vinay K.

doi:10.1128/jvi.00395-07

Cited by 204 publications

(321 citation statements)

References 44 publications

(68 reference statements)

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“…Most of our understanding about APOBEC3 activity and corresponding Vif defects has been gained by using overexpression systems (18,19,25). In this study, we demonstrate that HIV-1 Vif mutants with suboptimal anti-APOBEC3G activity display reduced fitness in a multiple round replication assay with human PBMCs.…”

Section: Table 1 Summary Of Hiv-1 Drug Resistance Mutations That Resmentioning

confidence: 77%

“…The two Vif mutants studied are located within the putative APOBEC3 interacting regions of Vif (25). In overexpression experiments these mutants display activity against APOBEC3F but no (K22E) or little (E45G) activity against APOBEC3G (18).…”

Section: Resultsmentioning

confidence: 99%

“…4A). (25,37,38,40). Each Vif mutation was introduced into the molecular clone HIV-1 NL4-3 and subsequently characterized.…”

Section: Genotypic and Phenotypic Characterization Of Proviruses Derivedmentioning

confidence: 99%

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Cytidine deamination induced HIV-1 drug resistance

Mulder

Harari²,

Simon³

2008

Proc. Natl. Acad. Sci. U.S.A.

148

169

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The HIV-1 Vif protein is essential for overcoming the antiviral activity of DNA-editing apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3 (APOBEC3) cytidine deaminases. We show that naturally occurring HIV-1 Vif point mutants with suboptimal anti-APOBEC3G activity induce the appearance of proviruses with lamivudine (3TC) drug resistance-associated mutations before any drug exposure. These mutations, ensuing from cytidine deamination events, were detected in >40% of proviruses with partially defective Vif mutants. Transfer of drug resistance from hypermutated proviruses via recombination allowed for 3TC escape under culture conditions prohibitive for any WT viral growth. These results demonstrate that defective hypermutated genomes can shape the phenotype of the circulating viral population. Partially active Vif alleles resulting in incomplete neutralization of cytoplasmic APOBEC3 molecules are directly responsible for the generation of a highly diverse, yet G-to-A biased, proviral reservoir, which can be exploited by HIV-1 to generate viable and drug-resistant progenies.hypermutation ͉ reservoir ͉ diversity ͉ reverse transcription

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Section: Table 1 Summary Of Hiv-1 Drug Resistance Mutations That Resmentioning

confidence: 77%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Cytidine deamination induced HIV-1 drug resistance

Mulder

Harari²,

Simon³

2008

Proc. Natl. Acad. Sci. U.S.A.

148

169

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“…Consistent with the importance of acidic residues in human-A3G for HIV-1 Vif binding, a 'complementary' region harbouring positively charged residues at positions 14 and 17 in HIV-1 Vif (Asp-Arg-Met-Arg) appears to be important for the interaction (Schrofelbauer et al 2006). This region is not, however, sufficient for the interaction, and a hydrophobic motif between residues 40 and 44 in HIV-1 Vif also plays a central role (Russell & Pathak 2007).…”

Section: Vif Inhibits Apobec3g Function By Inducing Proteasomal Degramentioning

confidence: 99%

“…These shared features of A3G and A3F seemingly accord with the view that these are the most significant APOBEC enzymes in terms of natural HIV-1 infection (namely in humans). Interestingly, the sequence elements within HIV-1 Vif required for inhibition of A3G versus A3F differ from each other (Simon et al 2005;Tian et al 2006;Russell & Pathak 2007), implying that evolutionary pressures have selected for the ability to suppress both proteins. Moreover, A3G and A3F are both expressed in human CD4 T cells (the principal target for HIV-1 infection in vivo), further supporting the notion that both enzymes naturally encounter HIV-1, and that the virus must have evolved to evade the anti-viral activities of each of them.…”

Section: Anti-hiv-1 Phenotypes Of Diverse Human Apobec Proteinsmentioning

confidence: 99%

APOBEC proteins and intrinsic resistance to HIV-1 infection

Malim

2008

Phil. Trans. R. Soc. B

245

268

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Members of the APOBEC family of cellular polynucleotide cytidine deaminases, most notably APOBEC3G and APOBEC3F, are potent inhibitors of HIV-1 infection. Wild type HIV-1 infections are largely spared from APOBEC3G/F function through the action of the essential viral protein, Vif. In the absence of Vif, APOBEC3G/F are encapsidated by budding virus particles leading to excessive cytidine (C) to uridine (U) editing of negative sense reverse transcripts in newly infected cells. This registers as guanosine (G) to adenosine (A) hypermutations in plus-stranded cDNA. In addition to this profoundly debilitating effect on genetic integrity, APOBEC3G/F also appear to inhibit viral DNA synthesis by impeding the translocation of reverse transcriptase along template RNA. Because the functions of Vif and APOBEC3G/F proteins oppose each other, it is likely that fluctuations in the Vif–APOBEC balance may influence the natural history of HIV-1 infection, as well as viral sequence diversification and evolution. Given Vif's critical role in suppressing APOBEC3G/F function, it can be argued that pharmacologic strategies aimed at restoring the activity of these intrinsic anti-viral factors in the context of infected cells in vivo have clear therapeutic merit, and therefore deserve aggressive pursuit.

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