Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV broadly neutralizing antibody.

Treatment of HIV infection with either anti-retroviral therapy (ART) or neutralizing monoclonal antibodies (NAbs) leads to a reduction in HIV plasma virus. Both ART and NAbs prevent new rounds of viral infection but NAbs may have the additional capacity to accelerate the loss of virus-infected cells through Fc gamma receptor (FcgR) mediated effector functions, which should affect the kinetics of plasma virus decline. Here we formally test this premise in vivo by comparing the plasma virus response to a single dose treatment with either unmodified NAb or those with either reduced or augmented Fc function. When infused into viremic SHIV-infected rhesus macaques, there was a 21% difference in slope of plasma virus decline between wt NAb and NAb with reduced Fc function. NAb engineered to increase FcgRIII binding and improve ADCC in vitro resulted in arming of effector cells in vivo yet led to viral decay kinetics similar to NAbs with reduced Fc function. These studies show that the predominant mechanism of antiviral activity of HIV NAbs is through inhibition of viral entry, but that Fc function does contribute to the overall antiviral activity, making them unique from standard ART. However, these data also show that increased FcgRIII engagement is insufficient to improve in vivo virus clearance. Overall design: Fifteen rhesus macaques, infected with simian HIV, were treated with the wild-type neutralizing monoclonal antibody VRC07-523LS (n=5), antibody with the LALA mutations (n=5) or the antibody with the DEL mutations (n=5). Peripheral blood mononuclear cells were collected pre-infusion (-48h or –30min), 1h and 3 days after antibodies infusion. NK cells were flow-sorted from the peripheral blood mononuclear cells. RNA was extracted from 5000 NK cells and sequenced to determine their transcriptomic profiles. Samples from one animal (from the LALA group) were excluded for technical reason (sequenced on a different machine). In total, the dataset comprises of 42 samples.