Characterization of Conserved Motifs in HIV-1 Vif Required for APOBEC3G and APOBEC3F Interaction

He, Zhong; Zhang, Wenyan; Chen, Gongying; Xu, Rongzhen; Yu, Xiao Fang

doi:10.1016/j.jmb.2008.06.061

Cited by 117 publications

(132 citation statements)

References 62 publications

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“…In addition, we identified a region important for A3H-hapII neutralization that is not required for A3F or A3G neutralization. Studies conducted by us and others have determined that Vif1 also has distinct regions for the neutralization of A3F, A3G, and A3H-hapII (34)(35)(36)(37)(38)(39). It is important to point out that it cannot be concluded that these motifs that have been identified to be critical for interaction through mutational analyses are themselves directly involved in the protein-protein interactions.…”

Section: Discussionmentioning

confidence: 97%

“…Vif1 interacts with numerous host cell proteins to form a ubiquitin ligase complex consisting of cullin 5, elongin B, and elongin C (29), RING finger protein 2 (30,31), and CBF␤ (32,33). Further, Vif1 has several domains through which it binds APOBEC3 proteins, with some regions being specific for certain APOBEC3s (34)(35)(36)(37)(38)(39). For example, the 40 YRHHY 44 motif of Vif1 is known to play a critical role in inducing the degradation of A3G, while the 14 DRMR 17 region is known to be critical for inducing the degradation of A3C, A3D, and A3F (34).…”

mentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 97%

mentioning

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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“…Furthermore, conserved Trp residues 11 and 79 are required for the efficient suppression of the antiviral activity of hA3F but not that of hA3G (229). However, the 40YRHHY44 and 14DRMR17 motifs are not conserved among the HIV-2, SIVmac, and SIVAgm Vif proteins (88 (88,248). Those studies indicated that multiple motifs in the N-terminal region of Vif are involved in interactions with hA3G and hA3F.…”

Section: Vif Counteracts the Antiviral Activities Of Ha3g And Ha3fmentioning

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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“…Through this activity of Vif, HIV-1 can grow in T lymphocytes and macrophages, the two major targets cells of the virus. Extensive studies by us and others have revealed that HIV-1 Vif consists of two major functional domains with various motifs (2)(3)(4). HIV-1 Vif binds to APOBEC3G/APOBEC3F by its N -terminal region (2 -10), and degrades them through interaction with its C -terminal region (2,(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

“…HIV-1 Vif binds to APOBEC3G/APOBEC3F by its N -terminal region (2 -10), and degrades them through interaction with its C -terminal region (2,(11)(12)(13)(14). While Vif mediates proteasomal degradation of both APOBEC3 proteins, it binds to them differently via several distinct motifs (2)(3)(4)(5)(6)(7)(8)(9)(10). In some CD4 + cells such as H9, primary T lymphocytes, and macrophages that are non-permissive for HIV-1 without Vif, APOBEC3G/APOBEC3F are found to act against HIV-1.…”

Section: Introductionmentioning

confidence: 99%

Different interaction between HIV-1 Vif and its cellular target proteins APOBEC3G/APOBEC3F

et al. 2010

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Characterization of Conserved Motifs in HIV-1 Vif Required for APOBEC3G and APOBEC3F Interaction

Cited by 117 publications

References 62 publications

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

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

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

Different interaction between HIV-1 Vif and its cellular target proteins APOBEC3G/APOBEC3F

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