Background
The major barrier to HIV-1 cure is a small, stable pool of latently infected resting CD4+ T cells. Following cessation of antiretroviral therapy (ART), there is rapid, exponential viral rebound from this latent reservoir. Cure strategies aim to prevent viral rebound. Autologous neutralizing antibodies (aNAbs) have been shown to block outgrowth of a substantial but variable fraction of viruses in the latent reservoir of people with HIV (PWH). However, it is not known whether aNAbs can neutralize viruses persisting after long-term ART (>20 years).
Methods
We conducted TZM-bl neutralization assays with HIV-1 env pseudoviruses of inducible, replication-competent outgrowth viruses from 15 PWH on long-term ART (>14 years, mean 22 years). For comparison, we analyzed outgrowth viruses isolated from 12 PWH on intermediate ART (mean 7 years). Neutralization assays tested either contemporaneous aNAbs or one of three broadly neutralizing antibodies (bNAbs; VRC01, 10-1074, PGDM1400). To address waning antibody levels, neutralization assays were conducted with a tier 1 virus (SF162), and longitudinal IgG samples from study participants. In addition, antibody-dependent cellular cytotoxicity (ADCC) assays were performed with NK cells, participant pseudoviruses, and contemporaneous IgG.
Results
Most replication-competent viral isolates (76%) from PWH on long-term ART were resistant to neutralization by aNAb with IC50 values >100 ug/ml. The fraction of resistant isolates was significantly higher than that observed for PWH on intermediate ART (38%, p = <0.0001). In contrast, outgrowth viruses from both groups remained sensitive to bNAbs (median bNAb IC50: 0.9 to 1.5 ug/ml). Autologous IgG from 94% of long-term ART participants neutralized SF162 virus, indicating long-term persistence of neutralizing antibody responses. Longitudinal analysis revealed aNAb maturation, stability, and waning over long-term ART in different participants. We also observed ADCC activity in antibodies from PWH on long-term ART.
Conclusions
Our findings demonstrated increased resistance of outgrowth viruses to aNAbs over long-term ART, which was not fully explained by a decline in neutralizing antibody concentrations. This increased resistance may be driven partially by ADCC-mediated elimination of infected cells carrying aNAb-sensitive viruses, leaving only aNAb-resistant viruses which can contribute to viral rebound.
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