Background
Antiretroviral therapy initiation (ARTi) halts HIV-1 replication but cannot clear persistent reservoirs. ARTi during acute (within 60 days of acquisition) and early (between ~60 and 120 days) HIV-1 limits reservoir size and diversity and can preserve nascent autologous neutralizing antibody (anAb) responses that target the transmitted/founder (TF) virus and then gain potency and breadth over viral suppression to target later variants. In a cohort of acute and early ART-treated people with HIV-1 (PWH), we compared viral sequences and anAb sensitivities of plasma and reservoir viruses.
Methods
Within a subset of the UCSF Treat Acute cohort (n=7 PWH [2 acute-, 5 early-treated; 7 male, 0 female]; NCT02656511), single genome sequencing (SGS) of gp160 env from plasma at ARTi and PBMC provirus from 24 weeks of ART was performed; sequences were analyzed by maximum-likelihood amino acid phylogenetic trees on a per-participant basis. Select Envs were tested for neutralization sensitivity to longitudinal plasma IgG by TZM.bl assays. Chimeric Envs encoding select regions were generated to map anAb responses at the molecular level.
Results
221 SGS-derived envs were sampled (n=134 plasma, n=87 proviral) across the 7 participants. Phylogenetic analyses of acute-treated participants showed co-alignment of plasma and reservoir sequences. In early-treated participants, however, proviral env persisting at 24 weeks of ART were generally enriched at tree roots while plasma env from the time of ARTi were biased toward branch tips. In some participants, reservoir envs revealed large branches no longer sampled in the plasma. Thus, reservoir env allowed inference of earlier variants no longer or less frequently replicating at the time of ARTi. In a subset of early-treated participants, plasma IgG from the time of ARTi potently neutralized archived reservoir Envs while plasma variants were resistant; IgG from later timepoints neutralized both reservoir and plasma Envs. Using chimeric plasma-PBMC Envs, early anAb targets were mapped to specific variable regions in gp120.
Conclusions
At early ARTi, viruses replicating in the plasma are anAb-escape variants while the proviral reservoir sampled 24 weeks later reveals envs archived from acute HIV-1 through ARTi including the targets of initial anAb responses. Together, phylogenetic and phenotypic testing of paired ARTi plasma and archived reservoir enables tracking of virus-host evolution that can be exploited in curative immunotherapy and vaccine strategies.
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