Lower Viral Loads and Slower CD4+ T-Cell Count Decline in MRKAd5 HIV-1 Vaccinees Expressing Disease-Susceptible HLA-B*58:02

HLA class I alleles are an important predictor of disease course in human immunodeficiency virus type 1 (HIV-1) infection [1]. In sub-Saharan Africa, HLA-B*57, HLA-B*58:01, and HLA-B*81:01 are protective against disease progression, while HLA-B*18:01 and HLA-B*58:02 are associated with rapid progression [2–4]. One contributory factor is the role of HLA molecules in presenting particular epitopes to induce CD8+ T-cell responses against HIV-1. Gag-specific CD8+ T-cell responses are associated with lower viremia levels and are dominant in people with protective HLA alleles, such as HLA-B*57:03 [1, 5]. In contrast, disease-susceptible HLA alleles, such as HLA-B*58:02, typically present relatively ineffective non-Gag responses [6] associated with high viral set points [5]. This prompts the hypothesis that a successful vaccine might induce Gag-specific responses in subjects who would not target this protein in natural infection. Two recent randomized efficacy trials of the MRKAd5 subtype B HIV-1 Gag/Pol/Nef T-cell vaccine provide a unique opportunity to address this hypothesis [7, 8]. The first study, Step, was conducted in the Americas, Australia, and the Caribbean, where HIV-1 subtype B predominates [7]. Both interim and follow-up analyses reported vaccine-enhanced HIV-1 acquisition [7, 9]. The second trial, Phambili, tested the efficacy of the same vaccine in South Africa, where HIV-1 subtype C is endemic [8, 10]. Following Step discontinuation, Phambili was terminated 9 months into the study, having enrolled 801 subjects (27%) of the originally scheduled 3000 [10]. As in Step, the vaccine increased the risk of HIV-1 acquisition and did not reduce viremia levels in early infection [8, 10]. Post hoc Step studies, however, demonstrated lower viremia levels in vaccinees with a greater breadth of Gag-specific CD8+ T-cell activity [11], consistent with the notion of Gag-specific efficacy, but also suggested the possibility of lower viral loads in vaccinees expressing protective HLA alleles [12, 13]. To examine this question in a population substantially dissimilar in the HLA alleles expressed from that studied in Step, we here tested in the South African Phambili cohort the hypothesis that the MRKAd5 HIV-1 vaccine might indeed have an HLA-specific effect. Specifically, we hypothesized that subjects expressing HLA-B*58:02, the most prevalent HLA-B allele in South Africans [2, 5], might benefit from the MRKAd5 HIV-1 vaccine. The rationale was that the HLA-B*58:02–restricted CD8+ T-cell response is solely Env specific and, therefore, associated with poor immune control [5, 14]; HLA-B*58:02 indeed is strongly associated with rapid HIV-1 disease progression in southern Africa [2, 3, 6]. Hence, vaccine-mediated induction of Gag-specific responses in subjects expressing HLA-B*58:02 would, hypothetically, improve disease course in vaccinees who subsequently became HIV-1 infected. HLA-B*18:01, also strongly associated with rapid progression [2, 3], restricts a dominant CD8+ T-cell epitope in Nef [5]. Although Nef-specific CD8+ T-cell responses have also been associated with poor control of HIV-1 [5, 15–17], the immunodominance of the HLA-B*18:01–restricted CD8+ T-cell response might be unaffected by the MRKAd5 HIV-1 Gag/Pol/Nef vaccine. We set out, therefore, to investigate the impact of the MRKAd5 HIV-1 vaccine in the Phambili trial, particularly on the HLA-B*58:02–expressing individuals, to determine whether immune control of HIV-1 was improved in vaccinees who subsequently became infected. This study has limitations that we wish to highlight, including postrandomization bias, sample selection bias, and low subject numbers (see Discussion), but it provides potentially important insights into HLA-dependent vaccine effects on the postinfection disease course and immune response to HIV-1.