PLOS ONE. 2017 Nov 17; 12(11):e0185959.

PubMed ID: 29149197

Sieve analysis of breakthrough HIV-1 sequences in HVTN 505 identifies vaccine pressure targeting the CD4 binding site of Env-gp120

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

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.