Background
Analytic treatment interruption (ATI) studies utilizing broadly neutralizing antibody (bnAb) infusions are associated with delayed viral rebound if viruses found in the participants are sensitive to the bnAbs. Yet, viral sensitivity is typically evaluated only after the ATI has been conducted. For a future ATI that will enroll 35 participants from the RV254 Thai cohort, we screened HIV-1 sequences for sensitivity to the bnAbs that will be used in the ATI: PGDM1400LS and VRC07-523LS.
Methods
Plasma samples were sequenced via single genome amplification or the Pacific Biosciences single molecule real-time platform using unique molecular identifiers. Envelope (env) sequences were cloned and pseudoviruses with these Env were tested for neutralization sensitivity to bnAbs using IC80<1ug/mL as a cutoff.
Results
Among 649 participants enrolled during acute HIV-1 infection who initiated antiretroviral treatment (ART) within days of diagnosis, 168 (98% male) met study eligibility criteria and 39,907 env sequences were obtained from 160 participants. Most participants had CRF01_AE env (85%). Sequence analysis showed minimal diversity (average mean pairwise diversity=0.004) with a single HIV-1 lineage in most participants (61%). Half of the infections with multiple founder lineages showed rare lineages that represented <3% of the viral population. For each participant, in silico predictions of bnAb sensitivity were used to select representative env sequences for neutralization assays. Neutralization data from 116 participants showed 54 (46.5%) sensitive to PGDM1400LS, 55 (46.7%) sensitive to VRC07-523LS, and 25 (21.5%) sensitive to both. We also modeled the Instantaneous Inhibitory Potential (IIP) values; at week 20 post ATI, 75 participants had clones with IIP (PGDM1400 + VRC07)>3.5, allowing prioritization of participants for study enrolment.
Conclusions
We developed a strategy combining sequence analysis, in silico bnAb sensitivity predictions and neutralization assays to prioritize enrollment of participants with the most sensitive viruses to the bnAbs that will be used in an ATI. Our approach benefitted from the fact that participants initiated ART in acute infection and therefore had a typically homogeneous viral reservoir recapitulated by the limited number of distinct env sequences we sampled. While the benefits of this approach will only be ascertained after the ATI is conducted, these data provide the largest description of sensitivity to two potent bnAbs across CRF01_AE viruses.
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