Anti-APOBEC3G activity of HIV-1 Vif protein is attenuated in elite controllers

• Published in: Journal of virology Vol. 89; no. 9; pp. 4992 - 5001
• Main Authors: Kikuchi, Tadashi, Iwabu, Yukie, Tada, Takuya, Kawana-Tachikawa, Ai, Koga, Michiko, Hosoya, Noriaki, Nomura, Shigeru, Brumme, Zabrina L, Jessen, Heiko, Pereyra, Florencia, Trocha, Alicja, Walker, Bruce D, Iwamoto, Aikichi, Tokunaga, Kenzo, Miura, Toshiyuki
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.05.2015
• Subjects: APOBEC-3G Deaminase; Cell Line; Cytidine Deaminase - antagonists & inhibitors; Cytidine Deaminase - immunology; Gene Expression Profiling; Genes, Reporter; Genetic Vectors; HIV Infections - immunology; HIV-1 - immunology; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Luciferases - analysis; Luciferases - genetics; Molecular Sequence Data; Polymorphism, Genetic; RNA, Viral - genetics; Sequence Analysis, DNA; Vesicular stomatitis virus; Vesiculovirus - genetics; vif Gene Products, Human Immunodeficiency Virus - genetics; vif Gene Products, Human Immunodeficiency Virus - metabolism; Virus-Cell Interactions
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/jvi.03464-14

HIV-1-infected individuals who control viremia to below the limit of detection without antiviral therapy have been termed elite controllers (EC). Functional attenuation of some HIV-1 proteins has been reported in EC. The HIV-1 accessory protein Vif (virion infectivity factor) enhances viral infectivity through anti-retroviral factor apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G (APOBEC3G) degradation; however, little is known regarding Vif function in EC. Here, the anti-APOBEC3G activities of clonal, plasma HIV RNA-derived Vif sequences from 46 EC, 46 noncontrollers (NC), and 44 individuals with acute infection (AI) were compared. Vesicular stomatitis virus glycoprotein (VSV-G)-pseudotyped viruses were generated by cotransfecting 293T cells with expression plasmids encoding patient-derived Vif, human APOBEC3G, VSV-G, and a vif/env-deficient luciferase-reporter HIV-1 proviral DNA clone. Viral stocks were used to infect 293T cells, and Vif anti-APOBEC3G activity was quantified in terms of luciferase signal. On average, the anti-APOBEC3G activities of EC-derived Vif sequences (median log10 relative light units [RLU], 4.54 [interquartile range {IQR}, 4.30 to 4.66]) were significantly lower than those of sequences derived from NC (4.75 [4.60 to 4.92], P < 0.0001) and AI (4.74 [4.62 to 4.94], P < 0.0001). Reduced Vif activities were not associated with particular HLA class I alleles expressed by the host. Vif functional motifs were highly conserved in all patient groups. No single viral polymorphism could explain the reduced anti-APOBEC3G activity of EC-derived Vif, suggesting that various combinations of minor polymorphisms may underlie these effects. These results further support the idea of relative attenuation of viral protein function in EC-derived HIV sequences. HIV-1 elite controllers (EC) are rare individuals who are able to control plasma viremia to undetectable levels without antiretroviral therapy. Understanding the pathogenesis and mechanisms underpinning this rare phenotype may provide important insights for HIV vaccine design. The EC phenotype is associated with beneficial host immunogenetic factors (such as HLA-B*57) as well as with functions of attenuated viral proteins (e.g., Gag, Pol, and Nef). In this study, we demonstrated that HIV-1 Vif sequences isolated from EC display relative impairments in their ability to counteract the APOBEC3G host restriction factor compared to Vif sequences from normal progressors and acutely infected individuals. This result extends the growing body of evidence demonstrating attenuated HIV-1 protein function in EC and, in particular, supports the idea of the relevance of viral factors in contributing to this rare HIV-1 phenotype.