Genetic analysis of breakthrough infections in people vaccinated against HIV-1 show that vaccine efficacy increased by up to 80% against viruses carrying two mutations in Env V2, but also raises the possibility of population-level adaptation to the vaccine. A major clinical trial involving more than 16,000 volunteers, known as the RV144 trial, tested a combination of two vaccines (ALVAC-HIV and AIDSVAX B/E gp120) for its ability to prevent HIV infection, as well as for safety. The vaccine was 31% effective against HIV-1 infection, and antibodies against the HIV-1 envelope variable loop 1 and 2 (V1/V2) domain correlated inversely with infection risk. Rolland et al. present a genetic analysis of breakthrough infections in RV144 trial participants and identify signatures associated with vaccine-induced immune pressure, thereby gaining support for a causal relationship between vaccination and protection. Viral amino-acid changes at positions 169 and 181 in the second variable loop of the viral envelope are shown to be most associated with efficacy — and represent possible targets for future vaccines. The RV144 trial demonstrated 31% vaccine efficacy at preventing human immunodeficiency virus (HIV)-1 infection1. Antibodies against the HIV-1 envelope variable loops 1 and 2 (Env V1 and V2) correlated inversely with infection risk2. 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.

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