Background
In people living with HIV on suppressive ART, the latent reservoir is composed of archived viral variants that are either sensitive or resistant to autologous neutralizing antibodies (aNAbs), with the latter capable of causing rebound following treatment interruption. We hypothesized ART-free virologic control might be achieved if aNAbs developed to neutralize all inducible, replication-competent reservoir variants. Study participant ID107 enrolled in the eCLEAR trial received broadly neutralizing antibody 3BNC117 and latency reversing agent romidepsin shortly after ART initiation, which was 2 months after HIV acquisition. He underwent an analytical treatment interruption 400 days after ART initiation and has maintained ART-free HIV remission for >6 years despite lacking protective HLA alleles. We characterized the aNAb response for this participant.
Methods
Quantitative viral outgrowth assays (QVOA) were conducted to obtain inducible, replication-competent reservoir viruses. Env sequences from outgrowth viruses were tested for sensitivity to aNAbs in pseudovirus neutralization assays with IgGs isolated from plasma collected at 12 longitudinal timepoints. Partial env sequences [HXB2: 827-1835] were obtained from plasma collected 5.4 years off ART. Soluble, stabilized Env trimers resembling autologous Env were purified for biochemical and structural analysis.
Results
The frequency of CD4+ T cells with inducible, replication-competent virus was 0.34 infectious units per million (IUPM), consistent with previous IUPM values obtained during ATI. Residual viremia env sequences were identical to most of the pre-ART viruses and many outgrowth viruses identified during the study. aNAbs from 11 timepoints readily neutralized autologous pseudoviruses (IC50 0.39- 5.2 μg/mL) but not heterologous viruses. To further characterize the aNAb responses, we calculated the instantaneous inhibitory potential (IIP), a measure of the number of logs of single round infection events inhibited at a given therapeutic dose. At average human serum IgG concentration (10 mg/mL), this participant’s aNAbs mediated a 5-7 log reduction in new infection events, comparable to many ART regimens. A 5.6 Å cryoEM structure of unliganded ID107 Env was obtained.
Conclusions
This participant has maintained ART-free remission for >6 years despite a reservoir size in the normal range. The aNAb responses that developed may contribute to the prolonged ART-free remission of study participant ID107.
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