Genetic impact of vaccination on breakthrough HIV-1 sequences from the STEP trial

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Abstract
The STEP HIV-1 vaccine trial failed to protect volunteers from infection, but whether vaccine-driven immune responses affected the profile of viral variants in infected individuals was unknown. By analyzing nucleotide sequences and predicted T cell epitopes in viruses from newly infected trial participants, Rolland et al. now report that the degree of viral divergence from vaccine-encoded inserts suggests that vaccine-induced T cell responses indeed influenced the viral repertoire, a finding that might be harnessed in future vaccine design. We analyzed HIV-1 genome sequences from 68 newly infected volunteers in the STEP HIV-1 vaccine trial. To determine whether the vaccine exerted selective T cell pressure on breakthrough viruses, we identified potential T cell epitopes in the founder sequences and compared them to epitopes in the vaccine. We found greater distances to the vaccine sequence for sequences from vaccine recipients than from placebo recipients. The most significant signature site distinguishing vaccine from placebo recipients was Gag amino acid 84, a site encompassed by several epitopes contained in the vaccine and restricted by human leukocyte antigen (HLA) alleles common in the study cohort. Moreover, the extended divergence was confined to the vaccine components of the virus (HIV-1 Gag, Pol and Nef) and not found in other HIV-1 proteins. These results represent what is to our knowledge the first evidence of selective pressure from vaccine-induced T cell responses on HIV-1 infection in humans.