Opi S, Kao S, Goila-Gaur R, Khan MA, Miyagi E, Takeuchi H, Strebel K. sequences. IMPORTANCE 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 3,3′-Diindolylmethane to this rare HIV-1 phenotype. INTRODUCTION HIV-1-infected individuals who control viremia to below the limit of detection ( 50 RNA copies/ml plasma) without antiretroviral therapy have been termed elite controllers 3,3′-Diindolylmethane (EC) (1, 2), while those with prolonged survival are known as slow progressors (SP) or long-term nonprogressors (LNTP). Although the mechanisms underlying these protective phenotypes remain incompletely understood, host genetics, innate and adaptive immune responses, and viral sequence variation represent likely contributors (1, 3, 4). Immunologic and host genetic factors associated with slower HIV disease progression include heterozygosity for a 32-bp deletion in the CCR5 gene (5), expression of particular HLA class I alleles (especially HLA-B*57 and B*27) (2, 6,C9), ability to mount Gag-specific cytotoxic T lymphocyte (CTL) responses (10,C12), quality of HIV-specific CTLs (13) or of CD4+ T lymphocytes (14), and epistatic interactions between HLA-Bw4 and NK cell receptor KIR3DS1 (15). However, these factors incompletely explain elite control. Viral factors also affect HIV-1 disease progression and/or set-point viral load. For example, deletions in the gene have been described in some LTNPs (16, 17). Furthermore, reduced entry efficiency of EC-derived sequences (18), reduced protein functions of genes (19), and reduced replication capacity of recombinant virus expressing EC-derived and sequences (20, 21) have been reported in EC, including at the earliest stages of infection (22). Together, these data support virologic factors as additional determinants of elite control and suggest a potentially important role of genotypic and/or functional characteristics of the transmitted virus in the infection course. However, the contribution of genetic and/or functional properties of other HIV accessory proteins to the controller phenotype remains unknown. Vif (virion infectivity factor) is an accessory protein that is essential for HIV-1 infectivity in primary CD4+ T lymphocytes (23). This viral protein mediates the degradation of the endogenous antiretroviral factor apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G (APOBEC3G) 3,3′-Diindolylmethane in virus-producing cells (24,C27). APOBEC3G belongs to the APOBEC family of proteins possessing cytidine deaminase activity (28). In the absence of Vif, APOBEC3G induces DIAPH2 a high rate of C-to-U lesions in the first minus strand of cDNA during the process of reverse transcription. This leads to G-to-A hypermutation in the plus-strand DNA, resulting in a potent restriction of viral infectivity (29, 30). Vif inhibits the lethal incorporation of APOBEC3G into virions by targeting it for ubiquitin-mediated degradation in virus-producing cells, via a mechanism involving the assembly of the Cullin5-ElonginB-ElonginC E3 ubiquitin 3,3′-Diindolylmethane ligase complex (31, 32). Though some studies have reported the presence of mutated or defective sequences in LTNPs (33,C36), the relationship between Vif genotypic/phenotypic variation and HIV disease progression remains incompletely characterized. In the present study, the anti-APOBEC3G activity of Vif proteins derived from HIV-1-infected elite controllers was compared to the anti-APOBEC3G activity of those from noncontrollers (NC) and from individuals with acute infection (AI). We observed significant attenuation of anti-APOBEC3G activity of Vif proteins derived from EC that did not appear to be attributable to a common single viral genetic defect in these patients. MATERIALS AND METHODS Study subjects and plasma collection. The EC, AI, and NC cohorts have been described in detail elsewhere (10, 20, 37, 38). Briefly, EC were defined as having plasma HIV-1 RNA levels of 50 copies/ml in the absence of antiretroviral.