Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env V2

Abstract

The RV144 trial demonstrated 31% vaccine efficacy at preventing human immunodeficiency virus (HIV)-1 infection. Antibodies against the HIV-1 envelope variable loops 1 and 2 (Env V1 and V2) correlated inversely with infection risk. We proposed that vaccine-induced immune responses against V1/V2 would have a selective effect against, or sieve, HIV-1 breakthrough viruses. A total of 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 V2 at amino acid positions 169 and 181. Vaccine efficacy against viruses matching the vaccine at position 169 was 48% (confidence interval 18% to 66%; P = 0.0036), whereas vaccine efficacy against viruses mismatching the vaccine at position 181 was 78% (confidence interval 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 signature sites (21 ± 7 Å) and their match/mismatch dichotomy indicate 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 had a role in the partial protection conferred by the RV144 regimen.

Figure 1

Phylogenetic tree of env-V1/V2 nucleotide sequences with highlights for sequences presenting mutations at either site 169 (in pink) or 181 (in yellow) or at both sites (in grey). Sequences from vaccine recipients are figured in red, those from placebo recipients are in blue.

Figure 2

Bar graphs representing the mutations at positions 169 and 181 based on sequences from 44 vaccine and 66 placebo recipients, with p- and q-values corresponding to the site-scanning sieve analysis method GWJ. The values correspond to comparisons against the 92TH023 vaccine insert based on the selected sites identified through the `contact residues' approach. Pre-specified p-value and q-value significance thresholds of .05 and .2, respectively. Full results in Supplementary Table S3.