Background:
A lead strategy for preventing HIV transmission is the passive provision of broadly neutralizing antibodies (bNAbs). Various investigators have validated this approach in nonhuman primate (NHP) models of HIV exposure. Experiments in NHPs have primarily focused on preventing viral transmission across anogenital mucosae. In humans, the antibody-mediated prevention (AMP) trial demonstrated that passively administered VRC01 bNAb prevents the transmission of neutralization-sensitive but not resistant HIV strains, emphasizing the urgent need for bNAbs with greater breadth and potency for immunoprophylaxis strategies.
Methods:
We developed a nonhuman primate model of immunoprophylaxis in the context of high-dose intravenous HIV exposure. We assessed the 10e8.4/iMAb bispecific antibody, which targets the membrane-proximal external region of the HIV envelope and the CD4 receptor, as an immunoprophylaxis agent. We measured the in vitro neutralization activity of 10e8.4/iMAb using the TZM-bl cell line-based neutralization assay. We intravenously infused three animals with 30mg/kg of 10e8.4/iMAb and three control animals with PBS. One hour later, we challenged all animals intravenously with a high dose (~50,000 TCID50) of SHIV-BG505. We performed antibody-mediated CD8+ lymphocyte depletions eight weeks after the viral challenge in aviremic animals to assess for subclinical/occult infections.
Results:
The SHIV-BG505 challenge virus was sensitive to 10e8.4/iMAb (IC50 <0.01 ug/ml). Control animals developed plasma viremia one week after high-dose intravenous viral challenge (peak: 8.7E6 – 1.1E7 copies/ml). Animals passively administered 10e8.4/iMAb exhibited no evidence of viral infection, even five weeks after systemic depletion of CD8+ lymphocytes.
Conclusions:
Passive intravenous provision of potent anti-HIV bispecific bNAbs is a highly promising immunoprophylaxis strategy for high-dose intravenous HIV exposure.