Administration of anti-HIV-1 broadly neutralizing monoclonal antibodies with increased binding affinity to Fcg receptors during acute SHIV infection shapes innate and adaptive cellular immunity [set1]
Anti-HIV-1 broadly neutralizing antibodies (bNAbs) have the dual potential of mediating virus neutralization and antiviral effector functions through their Fab and Fc domains, respectively. So far, bNAbs with enhanced Fc effector functions in vitro have only been tested in NHPs during chronic simian-HIV (SHIV) infection. Here, we investigated the effects of administering in acute SHIVAD8-EO infection either wild-type (WT) bNAbs or bNAbs carrying the S239D/I332E/A330L (DEL) mutation, which increases binding to FcgRs. Emergence of plasma and lymph node (LN) virus was delayed in bNAb-treated monkeys and occurred earlier in monkeys given DEL bNAbs than in those given WT bNAbs, consistent with faster clearance of DEL bNAbs from plasma. DEL bNAb-treated monkeys had higher levels of circulating virus-specific IFNg single-producing and IFNg/MIP-1b double-producing CD8+ CD69+ T cells than the other groups. In LNs, WT bNAbs were evenly distributed between follicular and extrafollicular areas, but DEL bNAbs predominated in the latter. At week 8 post-challenge, LN monocytes and NK cells from DEL bNAb-treated monkeys upregulated proinflammatory signaling pathways and LN T cells downregulated TNF signaling via NF-kB. Overall, bNAbs with increased binding affinity to FcgRs shaped innate and adaptive cellular immunity, which may be important to consider in future strategies of passive bNAb therapy. Overall design: Bulk mRNA-Seq of 175 samples collected from 17 rhesus macaques infected with simian-HIV and then treated with a wild-type broadly neutralizing antibody (bNAb; VRC07-523-LS, n=6), a bNAb with the DEL mutation (n=6) or kept untreated (n=5). Lymph nodes were collected at three timepoints (pre-infusion, day 14 and week 8) and immune cells from five subsets were sorted and profilled by mRNA-Seq.