Co-administration of the anti-HIV-1 bNAbs 10-1074 and 3BNC117 to SHIV-infected monkeys at days 3, 10, and 17 post-challenge led to long-term CD8+ T cell-mediated control of infection in half of the monkeys (Nishimura et al., Nature, 2017). A possible mechanism behind virus control is that bNAbs form immune complexes with SHIV, leading to its cross-presentation to CD8+ T cells and more robust immune responses. Here, we studied the contribution of immune complexes to the antiviral effect of early bNAb therapy.
SHIVAD8-EO intrarectally-challenged NHPs were not treated (n=6) or treated at days 3, 10, and 17 post-challenge with either WT VRC07-523-LS and PGT121 (n=6) or their DEL mutants (n=6), which show increased binding to FcgRs in vitro.
Five each of the 6 untreated or WT bNAb-treated monkeys became infected, but WT bNAb-treated monkeys suppressed virus for the first 8-14 weeks post-challenge. Viremia occurred after plasma bNAb levels declined. However, upon rebound, the peak and set point viral loads in these monkeys were indistinguishable from the untreated monkeys up to 124 weeks post-challenge. In contrast, only 3 monkeys treated with the DEL bNAbs have rebounded so far. This occurred earlier than in the WT bNAb-treated monkeys (at 5-6 weeks post-challenge), associated with poor plasma pharmacokinetics of the DEL bNAbs. The other 3 DEL bNAb-treated monkeys have not rebounded 68 weeks post-challenge, despite absence of circulating bNAbs. Lymph node SIV-specific CD8+ T cell responses developed later in treated monkeys than in untreated animals, consistent with delayed plasma viremia upon bNAb therapy. RNA sequencing analysis of antigen-presenting cells from lymph nodes revealed that treated monkeys developed a specific transcriptomic profile at week 2 post-challenge that persisted in DEL bNAb-treated monkeys through week 8 but was absent in untreated and WT bNAb-treated monkeys at the same timepoint.
No long-term differences in viral control were observed between untreated and WT bNAb-treated monkeys but 3 DEL bNAb-treated aviremic monkeys have not rebounded and are being studied more in depth to determine if they are controlling or completely free of virus. RNA sequencing analysis will be expanded to CD8+ T cell subsets to determine the effect of bNAb treatment in cell populations downstream of antigen-presenting cells, and microscopy will be conducted to determine the presence and location of the virus and infused bNAbs in the lymph nodes of these animals.