SummaryThe RV144 trial demonstrated 31% vaccine efficacy (VE) at preventing HIV-1 infection1. Antibodies against the HIV-1 envelope variable loops 1 and 2 (V1/V2) domain correlated inversely with infection risk2. We hypothesized that vaccine-induced immune responses against V1/V2 would selectively impact, or sieve, HIV-1 breakthrough viruses. 936 HIV-1 genome sequences from 44 vaccine and 66 placebo recipients were examined. We show that vaccine-induced immune responses were associated with two signatures in V1/V2 at amino-acid positions 169 and 181. VE against viruses matching the vaccine at position 169 was 48% (CI: 18 to 66%; p=0.0036), whereas VE against viruses mismatching the vaccine at position 181 was 78% (CI: 35% to 93%; p=0.0028). Residue 169 is in a cationic glycosylated region recognized by broadly neutralizing and RV144-derived antibodies. The predicted distance between the two signatures sites (21±7 Å), and their match/mismatch dichotomy, suggest that multiple factors may be involved in the protection observed in RV144. Genetic signatures of RV144 vaccination in V2 complement the finding of an association between high V1/V2 binding antibodies and reduced risk of HIV-1 acquisition and provide evidence that vaccine-induced V2 responses plausibly played a role in the partial protection conferred by the RV144 regimen.

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 for sequences from vaccine recipients than from placebo recipients (p-values ranging from < 0.0001 to 0.09). The most significant signature site distinguishing vaccine from placebo recipients was Gag-84, a site encompassed by several epitopes contained in the vaccine and restricted by HLA alleles common in the cohort. Moreover, the extended divergence was confined to the vaccine components of the virus (Gag, Pol, Nef) and not found in other HIV-1 proteins. These results represent the first evidence of selective pressure from vaccine-induced T-cell responses on HIV-1 infection.

http://indra.mullins.microbiol.washington.edu/blast/viroblast.php.