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

Abstract

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.

Efficacy Trials and Progress of HIV Vaccines

“…Because this approach to assess the impact of the vaccine from the viewpoint of viruses penetrating injury, because they represent the other side of the coin of the associated immune response. The sieve analysis was conducted targeting viruses penetrate RV144 found that the vaccine-induced differential gain of HIV-1 on the basis of viral sequences in the region that V2 [80]. These data support the hypothesis that linked the responses V1/V2 with the protection of the vaccine-induced.…”

“…Investigators are also under study of the function of bNAbs and their development during the HIV-I infection. As a result, many bNAbs have been isolated from the patients who are chronically infected by HIV and also been under detailed study [80][81][82][83][84][85][86][87][88][89][90][91]. Although antigens which are performing the reaction of these antibodies have not been yet identified.…”

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

“…In outcomes like these, where protection is incomplete, the characterization of breakthrough variants can inform us about correlates of vaccine-mediated protection against acquisition (18,22,23). Here, we went one step further by testing the capacity of prechallenge antibodies to neutralize the exact Env variant that broke through to establish each infection.…”

Is Prime Boost Strategy a Promising Approach in HIV Vaccine Development?

“…IgG antibodies specific to the V1/V2 region of HIV-1 gp120 correlated with a decreased risk of infection with evidence of a virus sieve effect in infected vaccine recipients at this gp120 region [72,73]. Although the exact mechanism mediating protection by these antibodies in the trial is not yet known, they are thought to block T-cell associated integrin, a4b7, which is involved in HIV-1 entry in activated CD4+ T-cells [74,75].…”