Structural basis for hijacking CBF-β and CUL5 E3 ligase complex by HIV-1 Vif

. To determine the regions mediating sensitivity to Vif, we compared human APOBEC3F, which is HIV-1 Vif sensitive, with rhesus APOBEC3F, which is HIV-1 Vif resistant. Rhesus-human APOBEC3F chimeras and amino acid substitution mutants were tested for sensitivity to HIV-1 Vif. This approach identified the ␣3 and ␣4 helices of human APOBEC3F as important determinants of the interaction with HIV-1 Vif.

supporting

confidence: 77%

APOBEC3F Determinants of HIV-1 Vif Sensitivity

Land

Shaban

Evans

et al. 2014

“…The N terminus of HIV-1 Vif, particularly the amino acids W5, V7, I9, W11, W21, W38, G84, E88, W89, L106, and I107 (Fig. 6A), was critical for CBF-␤ binding (30,56,(58)(59)(60)(61). These amino acids were almost conserved among primate lentiviral Vifs (Fig.…”

Section: Cbf-␤-kd 293t Cell Generationmentioning

confidence: 97%

“…Primate lentiviral Vif assembles with CUL5 through a conserved HCCH Zn finger motif (21,56). However, non-primate lentiviral Vif-CUL5 interactions have been rarely studied.…”

Section: Discussionmentioning

confidence: 99%

Core-Binding Factor Subunit Beta Is Not Required for Non-Primate Lentiviral Vif-Mediated APOBEC3 Degradation

Zhu

Wang

et al. 2014

Viral infectivity factor (Vif) is required for lentivirus fitness and pathogenicity, except in equine infectious anemia virus (EIAV).Vif enhances viral infectivity by a Cullin5-Elongin B/C E3 complex to inactivate the host restriction factor APOBEC3. Corebinding factor subunit beta (CBF-␤) is a cell factor that was recently shown to be important for the primate lentiviral Vif function. Non-primate lentiviral Vif also degrades APOBEC3 through the proteasome pathway. However, it is unclear whether CBF-␤ is required for the non-primate lentiviral Vif function. In this study, we demonstrated that the Vifs of non-primate lentiviruses, including feline immunodeficiency virus (FIV), bovine immunodeficiency virus (BIV), caprine arthritis encephalitis virus (CAEV), and maedi-visna virus (MVV), do not interact with CBF-␤. In addition, CBF-␤ did not promote the stability of FIV, BIV, CAEV, and MVV Vifs. Furthermore, CBF-␤ silencing or overexpression did not affect non-primate lentiviral Vif-mediated APOBEC3 degradation. Our results suggest that non-primate lentiviral Vif induces APOBEC3 degradation through a different mechanism than primate lentiviral Vif. IMPORTANCEThe APOBEC3 protein family members are host restriction factors that block retrovirus replication. Vif, an accessory protein of lentivirus, degrades APOBEC3 to rescue viral infectivity by forming Cullin5-Elongin B/C-based E3 complex. CBF-␤ was proved to be a novel regulator of primate lentiviral Vif function. In this study, we found that CBF-␤ knockdown or overexpression did not affect FIV Vif's function, which induced polyubiquitination and degradation of APOBEC3 by recruiting the E3 complex in a manner similar to that of HIV-1 Vif. We also showed that other non-primate lentiviral Vifs did not require CBF-␤ to degrade APOBEC3. CBF-␤ did not interact with non-primate lentiviral Vifs or promote their stability. These results suggest that a different mechanism exists for the Vif-APOBEC interaction and that non-primates are not suitable animal models for exploring pharmacological interventions that disrupt Vif-CBF-␤ interaction.

“…Vif simultaneously binds to APOBEC3 and to a cellular ubiquitin ligase (cullin5 [Cul5]-elongin [Elo]B/C-Rbx)) through distinct amino acids motifs (13,14). This binding induces the polyubiquitination of both APOBEC3 and Vif, which are then targeted for proteasomal degradation (3,(15)(16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

Possible Footprints of APOBEC3F and/or Other APOBEC3 Deaminases, but Not APOBEC3G, on HIV-1 from Patients with Acute/Early and Chronic Infections

Armitage

Deforche

Welch

et al. 2014

Members of the apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like-3 (APOBEC3) innate cellular cytidine deaminase family, particularly APOBEC3F and APOBEC3G, can cause extensive and lethal G-to-A mutations in HIV-1 plusstrand DNA (termed hypermutation). It is unclear if APOBEC3-induced mutations in vivo are always lethal or can occur at sublethal levels that increase HIV-1 diversification and viral adaptation to the host. The viral accessory protein Vif counteracts APOBEC3 activity by binding to APOBEC3 and promoting proteasome degradation; however, the efficiency of this interaction varies, since a range of hypermutation frequencies are observed in HIV-1 patient DNA. Therefore, we examined "footprints" of APOBEC3G and APOBEC3F activity in longitudinal HIV-1 RNA pol sequences from approximately 3,000 chronically infected patients by determining whether G-to-A mutations occurred in motifs that were favored or disfavored by these deaminases. Gto-A mutations were more frequent in APOBEC3G-disfavored than in APOBEC3G-favored contexts. In contrast, mutations in APOBEC3F-disfavored contexts were relatively rare, whereas mutations in contexts favoring APOBEC3F (and possibly other deaminases) occurred 16% more often than average G-to-A mutations. These results were supported by analyses of >500 HIV-1 env sequences from acute/early infection. IMPORTANCECollectively, our results suggest that APOBEC3G-induced mutagenesis is lethal to HIV-1, whereas mutagenesis caused by APOBEC3F and/or other deaminases may result in sublethal mutations that might facilitate viral diversification. Therefore, Vifspecific cytotoxic T lymphocyte (CTL) responses and drugs that manipulate the interplay between Vif and APOBEC3 may have beneficial or detrimental clinical effects depending on how they affect the binding of Vif to various members of the APOBEC3 family.