Background:
During untreated infection, HIV-1 rapidly evolves to escape contemporaneous, autologous neutralizing antibodies (anAbs). At the time of ART initiation, archived reservoir isolates may be sensitive or resistant to anAbs. Factors such as time to rebound, and the genotype of rebound virus are difficult to predict amongst analytical treatment interruption (ATI) cohorts. Elucidating the factors that govern these phenomena can inform cure strategies aiming for ART-free virologic control. We hypothesize that (1) anAb-resistant virus detected in the reservoir prior to an ATI may be identical, or genetically similar, to virus that rebounds post ART, and (2) higher percentages of anAb-sensitive reservoir variants may be associated with a longer time to rebound post ART.
Methods:
Among 9 study participants who underwent an ATI without intervention, we measured inhibition of outgrowth by contemporaneous anAbs in a modified quantitative viral outgrowth assay (mQVOA). The mQVOAs were conducted using donor-derived resting CD4+ T (rCD4) cells isolated prior to the ATI. These rCD4 cells were activated by PHA, then cultured in the presence of contemporaneous autologous IgG, HIV-negative donor IgG, or no IgG for 14 days. Viral outgrowth was scored by HIV-1 p24 ELISA.
Results:
With samples obtained prior to the ATI, we observed donor-to-donor variation in the ability of contemporaneous autologous IgG to neutralize inducible, replication-competent reservoir isolates. In the cohort analyzed, the fraction of outgrowth isolates neutralized by anAbs ranged from 0 to 44%, and it was observed that participants with more neutralizable reservoir variants had delayed times to viral rebound. Overall, the fraction of anAb-sensitive viruses detected in the latent HIV-1 reservoir prior to ART interruption significantly correlates (p=0.0150) with the time to viral rebound.
Conclusions:
We report that autologous IgG antibodies can neutralize inducible, replication-competent HIV-1 prior to an ATI, and higher percentages of variants susceptible to anAbs are associated with a longer time to rebound post ART. These results suggest that inducing a potent immune response against anAb-resistant virus could eventually lead to sustained virological control in the absence of ART. The mQVOA may serve as a useful pre-screening tool for selective ATI enrollment. Lastly, ATI studies using time to viral rebound as an outcome measurement should consider the anAb response when designing trials and interpreting results.