Virology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892;
Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 2020 Aug 4;117(31):18754-18763. doi: 10.1073/pnas.2008236117. Epub 2020 Jul 20.
Treatment of HIV infection with either antiretroviral (ARV) therapy or neutralizing monoclonal antibodies (NAbs) leads to a reduction in HIV plasma virus. Both ARVs 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 (FcγR)-mediated effector functions, which should affect the kinetics of plasma-virus decline. Here, we formally test the role of effector function in vivo by comparing the rate and timing of plasma-virus clearance in response to a single-dose treatment with either unmodified NAb or those with either reduced or augmented Fc function. When infused into viremic simian HIV (SHIV)-infected rhesus macaques, there was a 21% difference in slope of plasma-virus decline between NAb and NAb with reduced Fc function. NAb engineered to increase FcγRIII binding and improve antibody-dependent cellular cytotoxicity (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 can contribute to the overall antiviral activity, making them distinct from standard ARVs.
采用抗逆转录病毒（ARV）疗法或中和单克隆抗体（NAb）治疗 HIV 感染可降低 HIV 血浆病毒载量。ARV 和 NAb 均可防止新的病毒感染循环，但 NAb 可能通过 Fcγ 受体（FcγR）介导的效应功能加速感染病毒的细胞丢失，这应该会影响血浆病毒下降的动力学。在这里，我们通过比较单次剂量治疗后对未修饰的 NAb 或 Fc 功能降低或增强的 NAb 的血浆病毒清除率的速率和时间，来正式测试效应功能在体内的作用。当将其输注到携带病毒的灵长类动物 HIV（SHIV）感染的恒河猴中时，NAb 和 Fc 功能降低的 NAb 之间的血浆病毒下降斜率存在 21%的差异。在体外增加 FcγRIII 结合并改善抗体依赖性细胞毒性（ADCC）的 NAb 设计导致体内效应细胞的武装，但导致与 Fc 功能降低的 NAb 相似的病毒衰减动力学。这些研究表明，HIV NAb 的抗病毒活性的主要机制是通过抑制病毒进入，但 Fc 功能可以有助于整体抗病毒活性，使它们有别于标准的 ARV。
