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

Abstract

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.

Fc Gamma Receptor Polymorphisms Modulated the Vaccine Effect on HIV-1 Risk in the HVTN 505 HIV Vaccine Trial

“…The case-only method (65) was employed to assess whether and how each Fc␥R SNP modified the vaccine/placebo hazard ratio of HIV-1 acquisition risk (HR) between week 28 and month 24. The case-only method was also used to assess whether and how each Fc␥R SNP modified the hazard ratio of Env sequence-specific HIV-1 acquisition risk studied in the sieve analysis (13).…”

“…While this trial was unblinded early due to lack of overall VE, recent studies identified several correlates of HIV-1 acquisition risk in HVTN 505, including Env-specific CD8 ϩ T-cell response magnitude and polyfunctionality score (PFS) (11), Env-specific humoral IgG responses (12) and antibody Fc effector functions (antibody-dependent cellular phagocytosis [ADCP] and Fc␥RIIa binding) (76). Moreover, the vaccine/placebo hazard ratio of HIV-1 acquisition significantly varied by the type of HIV-1 virus, defined by amino acid sequence distance of the HIV-1 CD4 binding site to the vaccine insert sequence, a "sieve effect" (13). Cumulatively, these findings suggest that the DNA/rAd5 vaccine regimen has had differential effects on HIV-1 acquisition depending on immunologic and virologic markers.…”

“…To test this hypothesis, we genotyped HVTN 505 HIV-1-infected cases and uninfected controls (including both vaccine and placebo recipients) for Fc␥R genes, as previously described for RV144 cases and controls (8). We assessed whether and how Fc␥R SNPs were modified according to (i) the vaccine/placebo HR of HIV-1 acquisition risk, (ii) the previously identified associations of immune response biomarkers or Fc effector functions with HIV-1 acquisition risk in vaccine recipients (11,12), (iii) vaccineinduced immune responses, including Fc effector functions in vaccine recipients, and (iv) the previously identified Env-gp120 sieve effects (13). We also investigated the potential functional mechanisms of the identified Fc␥R SNPs by investigating their associations with Fc␥R expression in human B cells.…”

Striking a balance in an antibody network: A roadmap for HIV-1 vaccines

“…There was no effect of the vaccine on acquisition of HIV-1 infection. However, the vaccine left a footprint of immune pressure on the Env protein of breakthrough variants (8). Further, it elicited a high rate of antibody-dependent cellular phagocytosis (ADCP) with a broad dynamic range (8).…”

“…However, the vaccine left a footprint of immune pressure on the Env protein of breakthrough variants (8). Further, it elicited a high rate of antibody-dependent cellular phagocytosis (ADCP) with a broad dynamic range (8). To identify immune risk correlates, the authors used a case-control strategy in which they compared immune measures between 125 uninfected and 25 infected vaccine recipients, sampled at 4 weeks after the final rAd5 immunization (6).…”