Background
CD4 downregulation on HIV-1–infected cells impairs their elimination via ADCC by preventing non-neutralizing antibodies (nnAbs) from binding CD4-induced epitopes in Env. CD4-mimetic compounds (CD4mc) can expose these epitopes and restore ADCC. CJF-III-288 is a small CD4 mimetic compound (mc) that binds within the Phe43 cavity of gp120 “opening-up” Env, thereby allowing CD4-induced (CD4i) nnAbs binding and restoring ADCC-mediated killing. In this study, we evaluated CJF-III-288 treatment in SHIV-AD8–infected rhesus macaques (RMs).
Methods
Twelve RMs were infected with SHIV-AD8-EO. At day 36 post-infection (p.i.), six animals received CJF-III-288 (36 mg/kg, 5 doses, every 3 days) plus a single dose of simianized A32 and 17b nnAbs (20 mg/kg), while six controls received only the nnAbs. Antiretroviral therapy (ART) was initiated at day 43 and interrupted at day 209 p.i. At day 7 post- Analytical Treatment Interruption (ATI), the same regimen was repeated. Plasma viral load (PVL) was quantified by RT-qPCR, and intact proviral DNA by IPDA in sorted CD4+ T-cells from lymph nodes.
Results
CJF-III-288 was well tolerated, with only transient alanine aminotransferase (ALT) elevation restored to normal levels at the end of the dosing regimen. At day 43 p.i., animals receiving CD4mc+nnAbs showed a faster PVL reduction compared to nnAbs-only controls (fold-change d43/d35 p.i.: 0.5±0.25 vs 1.0±0.4). Similarly, intact proviral DNA in CD4 T cells from lymph nodes was reduced in CD4mc+nnAbs RMs compared to controls (fold-change d43/d28 p.i.: 0.60±0.09 vs 1.07±0.23). The extent of these reductions in PVL and intact SIV-DNA were insufficient to impact on the time or extent of viral rebound following ATI.
Conclusions
These results confirm the safety and biological activity of the CJF-III-288 in the RMs model, with a modest but measurable effect in reducing the levels of infected CD4+ T-cells. Ongoing NK assay to measure ADCC activity will provide mechanistic data. These findings inform and provide rationale for studies combining more potent CD4mc with NK-activating factors (e.g. IL-21 or IL-15) in RMs.