Potent suppression of viral rebound after analytical treatment interruption in ART-suppressed SHIV-infected animals by a CD4 binding site bNAb

Abstract

Abstract Broadly neutralizing antibodies (bNAbs) are promising immunotherapeutic biological agents against HIV-1 that can be used to complement small-molecule combination antiretroviral therapy (cART) drugs for the treatment of HIV-1 infection. There have been several analytical treatment interruption (ATI) studies utilizing bNAbs in ART-suppressed HIV-1-infected patients in which bNAbs are infused during an ART cessation period. To model these clinical studies, bNAbs can be administered to ART-suppressed SHIV-infected rhesus macaques (RM). However, delivery of human bNAbs to RMs induces formation of anti-drug antibodies (ADA) which shorten the half-life of the bNAb and limit the time during which effectiveness can be assessed. In this study, we infused six ART-suppressed SHIV-infected RMs with four 6–10 mg/kg doses of VRC01v23, a next generation CD4-binding site bNAb, every 2–4 weeks for a total duration of 10 weeks. Prior to bNAb treatment, three 50 mg/kg doses of an anti-CD20 antibody were given two weeks apart in order to deplete peripheral B cells and eliminate ADA. Five of six animals had persistent B cell depletion and showed no evidence of ADA after infusions of VRC01v23 and cessation of ART. No viral rebound was observed in these five animals. The sixth animal developed ADA against VRC01v23 resulting in rapid clearance of VRC01v23 from circulation and viral rebound. These data demonstrate that B cell depletion can limit the development of ADA against human bNAbs allowing for the assessment of long-term therapeutic potential of human bNAbs in RMs. Supported by intramural NIAID funding