Background:
ART initiation (ARTi) in acute/early HIV limits reservoir size and diversity, preserves host immunity, and limits transmission risk, but may also limit development of HIV-specific immune responses. While the kinetics of HIV-specific immunity with ongoing viremia is described, the effect of early ARTi on autologous neutralizing antibody (anAb) development and persistence is less clear. Here, we tested for antibody responses to the identified transmitted/founder (TF) or early virus populations in individuals with acute/early ARTi.
Methods:
Among 15 participants from the UCSF Treat Acute HIV study of individuals with acute/early ARTi, plasma was obtained at day of ARTi and longitudinally for 6-36 months. Single genome sequencing (SGS) of early plasma virus was used to identify TF viruses or representative early viruses, which were cloned and pseudotyped. Plasma IgG from longitudinal timepoints was used to test for autologous neutralization by TZM.bl assay. In parallel, plasma IgG was assessed for gp120-specific binding antibodies by ELISA and neutralization of tier 1 MN and SF162 strains.
Results:
SGS of gp160 env was performed on first available plasma from 15 participants with ARTi in Fiebig stages I-V and estimated date of diagnostic infection (EDDI) ranging from 17-128 days. SGS (n=311 total, median=22/participant) identified 8 single and 7 multiple virus transmissions. In all 15 participants, plasma IgG from the day of diagnosis/ARTi did not neutralize the contemporaneous autologous TF/early virus. In 7 participants with ARTi < 60 days from EDDI who maintained suppression on ART, no anAbs developed in up to 3 years of sampling. In contrast, 2 of 3 participants with EDDI < 60 days who experienced viral rebound (weeks 16 and 96 after ARTi) subsequently developed anAbs. In participants with ARTi at EDDI >60 days, 5 of 6 developed anAbs 12-80 weeks post-ARTi, which increased in potency on continued ART. AnAb potency at week 24 post-ARTi correlated with time to ARTi (r=-0.69, p=0.006), and with binding antibodies at ARTi (r=-0.79, p< 0.001) and 24 weeks later (r=-0.86, p< 0.0001).
Conclusions:
AnAbs developed only in those initiating ART >60 days after EDDI or following rebound viremia after initial ARTi, suggesting that anAb development is dependent on a threshold of viral exposure. In participants for whom this virus exposure threshold was met, anAb potency increased over years of suppressive ART. Results have implications for humoral immunotherapy approaches in PLWH with early ARTi.
Plasma IgG Neutralization of Transmitted/Founder or Early Virus. 