Sieve analysis of breakthrough HIV-1 sequences in HVTN 505 identifies vaccine pressure targeting the CD4 binding site of Env-gp120.
Although the HVTN 505 DNA/recombinant adenovirus type 5 vector HIV-1 vaccine trial showed no overall efficacy, analysis of breakthrough HIV-1 sequences in participants can help determine whether vaccine-induced immune responses impacted viruses that caused infection. We analyzed 480 HIV-1 genomes sampled from 27 vaccine and 20 placebo recipients and found that intra-host HIV-1 diversity was significantly lower in vaccine recipients (P ≤ 0.04, Q-values ≤ 0.09) in Gag, Pol, Vif and envelope glycoprotein gp120 (Env-gp120). Furthermore, Env-gp120 sequences from vaccine recipients were significantly more distant from the subtype B vaccine insert than sequences from placebo recipients (P = 0.01, Q-value = 0.12). These vaccine effects were associated with signatures mapping to CD4 binding site and CD4-induced monoclonal antibody footprints. These results suggest either (i) no vaccine efficacy to block acquisition of any viral genotype but vaccine-accelerated Env evolution post-acquisition; or (ii) vaccine efficacy against HIV-1s with Env sequences closest to the vaccine insert combined with increased acquisition due to other factors, potentially including the vaccine vector.
deCamp, AC; Rolland, M; Edlefsen, PT; Sanders-Buell, E; Hall, B; Magaret, CA; Fiore-Gartland, AJ; Juraska, M; Carpp, LN; Karuna, ST; Bose, M; LePore, S; Miller, S; O'Sullivan, A; Poltavee, K; Bai, H; Dommaraju, K; Zhao, H; Wong, K; Chen, L; Ahmed, H; Goodman, D; Tay, MZ; Gottardo, R; Koup, RA; Bailer, R; Mascola, JR; Graham, BS; Roederer, M; O'Connell, RJ; Michael, NL; Robb, ML; Adams, E; D'Souza, P; Kublin, J; Corey, L; Geraghty, DE; Frahm, N; Tomaras, GD; McElrath, MJ; Frenkel, L; Styrchak, S; Tovanabutra, S; Sobieszczyk, ME; Hammer, SM; Kim, JH; Mullins, JI; Gilbert, PB
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