7SL RNA Mediates Virion Packaging of the Antiviral Cytidine Deaminase APOBEC3G

Wang, Tao; Tian, Chunjuan; Zhang, Wenyan; Luo, Kun; Sarkis, Phuong Thi Nguyen; Yu, Lillian; Liu, Bindong; Yu, Yunkai; Yu, Xiaofang

doi:10.1128/jvi.00892-07

Cited by 143 publications

(215 citation statements)

References 82 publications

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“…Accordingly, A3G is not encapsidated by either HIV-1 virus-like particles that lack NC domains (Schafer et al 2004;Zennou et al 2004) or other retroviruses whose Gag proteins do not form complexes with A3G (Doehle et al 2006). The identity of the RNA(s) that promote A3G packaging in HIV-1 infected cells remains somewhat unresolved, though HIV-1 genomic RNA and 7SL RNA (a small pol III transcript that is found in the signal recognition particle, SRP) have each been assigned stimulatory roles in the process (Luo et al 2004;Khan et al 2005Khan et al , 2007Wang et al 2007). The fact that A3G is an avid RNA-binding protein ( Navarro et al 2005;Iwatani et al 2006) raises an important question concerning packaging: specifically, since A3G is associated with an array of cellular ribonucleoprotein (RNP) complexes in an RNA-dependent manner (Chiu et al 2005(Chiu et al , 2006Chelico et al 2006;Kozak et al 2006;Wichroski et al 2006;Gallois-Montbrun et al 2007), how can its RNA-binding site(s) be liberated to allow engagement with the RNA that facilitates packaging?…”

Section: The Packaging Of Apobec3g Into Hiv-1 Virionsmentioning

confidence: 99%

“…Specifically, amino acid substitutions at Tyr-124 or Trp-127 yield proteins that are severely debilitated for packaging into HIV-1 particles, and are therefore poor inhibitors of virus infection (Huthoff & Malim 2007;Wang et al 2007;Zhang et al 2007). More recent results indicate that these mutant proteins are also substantially deficient for RNA binding and are unable to form A3G-A3G dimers efficiently (H. Huthoff & M. H. Malim 2008, unpublished observations).…”

Section: The Packaging Of Apobec3g Into Hiv-1 Virionsmentioning

confidence: 99%

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APOBEC proteins and intrinsic resistance to HIV-1 infection

Malim

2008

Phil. Trans. R. Soc. B

239

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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Section: The Packaging Of Apobec3g Into Hiv-1 Virionsmentioning

confidence: 99%

Section: The Packaging Of Apobec3g Into Hiv-1 Virionsmentioning

confidence: 99%

APOBEC proteins and intrinsic resistance to HIV-1 infection

Malim

2008

Phil. Trans. R. Soc. B

239

268

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“…4A). APOBEC3G/3F expression and packaging efficiency (33) and single-nucleotide polymorphisms in the APOBEC3 genes could contribute to such an individual deamination threshold.…”

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

confidence: 99%

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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“…However, the P129D mutation confers resistance to Vif2, perhaps by inducing a conformational change that alters the structure of another distal domain that interacts with Vif2. To further analyze the region surrounding D128 in A3G, we determined the sensitivity of the A3G-W127A mutant, which has been shown to be deficient in virion incorporation (59)(60)(61). Because this mutant lacks antiviral activity, we tested the ability of Vif1 and Vif2 to induce the degradation of A3G-W127A by Western blotting (Fig.…”

Section: Yrhhymentioning

confidence: 99%

HIV-1 and HIV-2 Vif Interact with Human APOBEC3 Proteins Using Completely Different Determinants

Smith

Izumi

Borbet

et al. 2014

J Virol

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Human APOBEC3 (A3) restriction factors provide intrinsic immunity against zoonotic transmission of pathogenic viruses. A3D, A3F, A3G, and A3H haplotype II (A3H-hapII) can be packaged into virion infectivity factor (Vif)-deficient HIVs to inhibit viral replication. To overcome these restriction factors, Vif binds to the A3 proteins in viral producer cells to target them for ubiquitination and proteasomal degradation, thus preventing their packaging into assembling virions. Therefore, the Vif-A3 interactions are attractive targets for novel drug development. HIV-1 and HIV-2 arose via distinct zoonotic transmission events of simian immunodeficiency viruses from chimpanzees and sooty mangabeys, respectively, and Vifs from these viruses have limited homology. To gain insights into the evolution of virus-host interactions that led to successful cross-species transmission of lentiviruses, we characterized the determinants of the interaction between HIV-2 Vif (Vif2) with human A3 proteins and compared them to the previously identified HIV-1 Vif (Vif1) interactions with the A3 proteins. We found that A3G, A3F, and A3H-hapII, but not A3D, were susceptible to Vif2-induced degradation. Alanine-scanning mutational analysis of the first 62 amino acids of Vif2 indicated that Vif2 determinants important for degradation of A3G and A3F are completely distinct from these regions in Vif1, as are the determinants in A3G and A3F that are critical for Vif2-induced degradation. These observations suggest that distinct Vif-A3 interactions evolved independently in different SIVs and their nonhuman primate hosts and conservation of the A3 determinants targeted by the SIV Vif proteins resulted in successful zoonotic transmission into humans. IMPORTANCEPrimate APOBEC3 proteins provide innate immunity against invading pathogens, and Vif proteins of primate lentiviruses have evolved to overcome these host defenses by interacting with them and inducing their proteasomal degradation. HIV-1 and HIV-2 are two human pathogens that induce AIDS, and elucidating interactions between their Vif proteins and human A3 proteins could facilitate the development of novel antiviral drugs. Furthermore, understanding Vif-A3 interactions can provide novel insights into the cross-species transmission events that led to the HIV-1 and HIV-2 pandemics and evolution of host-virus interactions. We carried out mutational analysis of the N-terminal 62 amino acids of HIV-2 Vif (Vif2) and analyzed A3G/A3F chimeras that retained antiviral activity to identify the determinants of the Vif2 and A3 interaction. Our results show that the Vif2-A3 interactions are completely different from the Vif1-A3 interactions, suggesting that these interactions evolved independently and that conservation of the A3 determinants resulted in successful zoonotic transmission into humans.

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7SL RNA Mediates Virion Packaging of the Antiviral Cytidine Deaminase APOBEC3G

Cited by 143 publications

References 82 publications

APOBEC proteins and intrinsic resistance to HIV-1 infection

APOBEC proteins and intrinsic resistance to HIV-1 infection

Cytidine deamination induced HIV-1 drug resistance

HIV-1 and HIV-2 Vif Interact with Human APOBEC3 Proteins Using Completely Different Determinants

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