The Activity Spectrum of Vif from Multiple HIV-1 Subtypes against APOBEC3G, APOBEC3F, and APOBEC3H

Binka, Mawuena; Ooms, Marcel; Steward, Myeika; Simon, Viviana

doi:10.1128/jvi.06082-11

Cited by 89 publications

(118 citation statements)

References 53 publications

(84 reference statements)

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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%

“…Our results also indicate that A3H-hapII is efficiently degraded by the Vif2 used in our studies (derived from HIV-2 ROD12 ). Because A3H-hapII sensitivity to Vif1 is dependent on the subtype from which Vif1 is derived (35,72), it would be interesting to determine whether A3H-hapII is sensitive to other Vif2 variants as well.…”

Section: Discussionmentioning

confidence: 99%

“…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%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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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“…We generated a panel of 13 Vif mutants consisting of positively charged arginine and negatively charged glutamate at and around positions deemed important for A3H recognition based on previous work (Fig. 5A) (12)(13)(14)(15)(16) and tested their activity against selected Vif-resistant A3H mutants in single-cycle infectivity assays. We found that Vif-WT, Vif-G37R, and Vif-D61R efficiently counteracted A3H-WT, Vif mutants G37E, G60E, A62E, A62R, R63E, and R90E showed reduced anti-A3H activity, and Vif mutants F39E, F39R, E54R, H56E, and R93E completely lost their activity against A3H-WT (Fig.…”

Section: Identification Of the Vif Binding Site Of A3hmentioning

confidence: 99%

“…To date, only a single amino acid at position 121 in A3H has been implicated in the interaction with HIV Vif: mutating aspartic acid (D) at position 121 to a lysine (K) renders A3H resistant to Vif (14,15). On the Vif side, amino acid positions 39, 48, and 60 to 63 are important for the counteraction of A3H, indicating they are part of the A3H binding site (12,13,15,16).…”

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confidence: 99%

The Structural Interface between HIV-1 Vif and Human APOBEC3H

Ooms

Letko

Simon

2017

J Virol

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Human APOBEC3H (A3H) is a cytidine deaminase that inhibits HIV-1 replication. To evade this restriction, the HIV-1 Vif protein binds A3H and mediates its proteasomal degradation. To date, little information on the Vif-A3H interface has been available. To decipher how both proteins interact, we first mapped the Vifbinding site on A3H by functionally testing a large set of A3H mutants in singlecycle infectivity and replication assays. Our data show that the two A3H ␣-helixes ␣3 and ␣4 represent the Vif-binding site of A3H. We next used viral adaptation and a set of Vif mutants to identify novel, reciprocal Vif variants that rescued viral infectivity in the presence of two Vif-resistant A3H mutants. These A3H-Vif interaction points were used to generate the first A3H-Vif structure model, which revealed that the A3H helixes ␣3 and ␣4 interact with the Vif ␤-sheet (␤2-␤5). This model is in good agreement with previously reported Vif and A3H amino acids important for interaction. Based on the predicted A3H-Vif interface, we tested additional points of contact, which validated our model. Moreover, these experiments showed that the A3H and A3G binding sites on HIV-1 Vif are largely distinct, with both host proteins interacting with Vif ␤-strand 2. Taken together, this virus-host interface model explains previously reported data and will help to identify novel drug targets to combat HIV-1 infection.IMPORTANCE HIV-1 needs to overcome several intracellular restriction factors in order to replicate efficiently. The human APOBEC3 locus encodes seven proteins, of which A3D, A3F, A3G, and A3H restrict HIV-1. HIV encodes the Vif protein, which binds to the APOBEC3 proteins and leads to their proteasomal degradation. No HIV-1 Vif-APOBEC3 costructure exists to date despite extensive research. We and others previously generated HIV-1 Vif costructure models with A3G and A3F by mapping specific contact points between both proteins. Here, we applied a similar approach to HIV-1 Vif and A3H and successfully generated a Vif-A3H interaction model. Importantly, we find that the HIV-1 Vif-A3H interface is distinct from the Vif-A3G and Vif-A3F interfaces, with a small Vif region being important for recognition of both A3G and A3H. Our Vif-A3H structure model informs on how both proteins interact and could guide toward approaches to block the Vif-A3H interface to target HIV replication.KEYWORDS HIV-1, APOBEC3H, Vif, restriction factor, APOBEC3, A3H, HIV T he human APOBEC3 family consists of seven distinct proteins (A3A to A3H), several of which have potent activity against HIV-1 (1, 2). During infection of the new cell, virion-incorporated APOBEC3 proteins target the process of reverse transcription through directly deaminating the viral single-stranded DNA as well as by deaminaseindependent mechanisms (3-6). In turn, HIV-1 counteracts APOBEC3 restriction by

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Structural perspectives on HIV‐1 Vif and APOBEC3 restriction factor interactions

Azimi

Lee

2019

Protein Science

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Human immunodeficiency virus (HIV) is a retroviral pathogen that targets human immune cells such as CD4 + T cells, macrophages, and dendritic cells. The human apolipoprotein B mRNA-editing catalytic polypeptide 3 (APOBEC3 or A3) cytidine deaminases are a key class of intrinsic restriction factors that inhibit replication of HIV. When HIV-1 enters the cell, the immune system responds by inducing the activation of the A3 family proteins, which convert cytosines to uracils in singlestranded DNA replication intermediates, neutralizing the virus. HIV counteracts this intrinsic immune response by encoding a protein termed viral infectivity factor (Vif). Vif targets A3 to an E3 ubiquitin ligase complex for poly-ubiquitination and proteasomal degradation. Vif is unique in that it can recognize and counteract multiple A3 restriction factor substrates. Structural biology studies have provided significant insights into the overall architectures and functions of Vif and A3 proteins; however, a structure of the Vif-A3 complex has remained elusive. In this review, we summarize and reanalyze experimental data from recent structural, biochemical, and functional studies to provide key perspectives on the residues involved in Vif-A3 protein-protein interactions.

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The Activity Spectrum of Vif from Multiple HIV-1 Subtypes against APOBEC3G, APOBEC3F, and APOBEC3H

Cited by 89 publications

References 53 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

The Structural Interface between HIV-1 Vif and Human APOBEC3H

Structural perspectives on HIV‐1 Vif and APOBEC3 restriction factor interactions

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