Research Institute of the McGill University Health Centregrid.63984.30 (RI-MUHC), Montreal, Quebec, Canada.
Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
J Virol. 2021 Nov 23;95(24):e0162521. doi: 10.1128/JVI.01625-21. Epub 2021 Sep 29.
People living with HIV (PLWH) develop both anti-envelope-specific antibodies, which bind the closed trimeric HIV envelope present on infected cells, and anti-gp120-specific antibodies, which bind gp120 monomers shed by infected cells and taken up by CD4 on uninfected bystander cells. Both antibodies have an Fc portion that binds to Fc receptors on several types of innate immune cells and stimulates them to develop antiviral functions. Among these Fc-dependent functions (FcDFs) are antibody-dependent (AD) cellular cytotoxicity (ADCC), AD cellular trogocytosis (ADCT), and AD phagocytosis (ADCP). In this study, we assessed the evolution of total immunoglobulin G (IgG), anti-gp120, and anti-envelope IgG antibodies and their FcDFs in plasma samples from antiretroviral therapy (ART)-naive subjects during early HIV infection (28 to 194 days postinfection [DPI]). We found that both the concentrations and FcDFs of anti-gp120 and anti-envelope antibodies increased with time in ART-naive PLWH. Although generated concurrently, anti-gp120-specific antibodies were 20.7-fold more abundant than anti-envelope-specific antibodies, both specificities being strongly correlated with each other and FcDFs. Among the FcDFs, only ADCP activity was inversely correlated with concurrent viral load. PLWH who started ART at >90 DPI showed higher anti-envelope-specific antibody levels and ADCT and ADCP activities than those starting ART at<90 DPI. However, in longitudinally collected samples, ART initiation at >90 DPI was accompanied by a faster decline in anti-envelope-specific antibody levels, which did not translate to a faster decline in FcDFs than for those starting ART at <90 DPI. Closed-conformation envelope is expressed on the surface of HIV-infected cells. Antibodies targeting this conformation and that support FcDFs have the potential to control HIV. This study tracked the timing of the appearance and evolution of antibodies to closed-conformation envelope, whose concentration increased over the first 6 months of infection. Antiretroviral therapy (ART) initiation blunts further increases in the concentration of these antibodies and their and FcDFs. However, antibodies to open-conformation envelope also increased with DPI until ART initiation. These antibodies target uninfected bystander cells, which may contribute to loss of uninfected CD4 cells and pathogenicity. This report presents, for the first time, the evolution of antibodies to closed-conformation envelope and their fate on ART. This information may be useful in making decisions on the timing of ART initiation in early HIV infection.
人类免疫缺陷病毒（HIV）感染者（PLWH）会产生针对包膜蛋白特异性的抗体，这些抗体可以与感染细胞表面上的闭合三聚体 HIV 包膜结合，也会产生针对 gp120 单体特异性的抗体，这些抗体可以与被感染细胞释放的 gp120 单体结合，并被未感染的旁观者细胞上的 CD4 摄取。这两种抗体都有一个 Fc 部分，可以与几种类型的先天免疫细胞上的 Fc 受体结合，并刺激它们发挥抗病毒作用。在这些 Fc 依赖性功能（FcDFs）中，包括抗体依赖性（AD）细胞毒性（ADCC）、AD 细胞吞噬（ADCT）和 AD 吞噬（ADCP）。在这项研究中，我们评估了抗 gp120 和抗包膜 IgG 抗体及其 FcDFs 在接受抗逆转录病毒治疗（ART）的 HIV 感染者（ART-naive）在感染早期（感染后 28 至 194 天）的血浆样本中的演变情况。我们发现，在未经治疗的 PLWH 中，抗 gp120 和抗包膜抗体的浓度和 FcDFs 随时间推移而增加。虽然同时产生，但抗 gp120 特异性抗体的丰度比抗包膜特异性抗体高 20.7 倍，这两种特异性均与彼此呈强烈相关性，且与 FcDFs 呈强相关性。在 FcDFs 中，只有 ADCP 活性与同期病毒载量呈负相关。在 90 天以上开始 ART 的 PLWH 与在 90 天以下开始 ART 的 PLWH 相比，其抗包膜特异性抗体水平、ADCT 和 ADCP 活性更高。然而，在纵向收集的样本中，90 天以上开始 ART 会导致抗包膜特异性抗体水平更快下降，但与 90 天以下开始 ART 的患者相比，其 FcDFs 下降速度并没有更快。闭合构象的包膜表达于感染 HIV 的细胞表面。针对这种构象的抗体和支持 FcDFs 的抗体具有控制 HIV 的潜力。本研究跟踪了针对闭合构象包膜的抗体的出现和演变的时间，这些抗体的浓度在感染的前 6 个月内增加。抗逆转录病毒治疗（ART）的启动抑制了这些抗体及其 FcDFs 浓度的进一步增加。然而，在开始 ART 之前，针对开放构象包膜的抗体也随着时间的推移而增加。这些抗体针对未感染的旁观者细胞，这可能导致未感染的 CD4 细胞丢失和致病性增加。本报告首次介绍了针对闭合构象包膜的抗体的演变及其在 ART 中的命运。这些信息可能有助于在 HIV 早期感染时决定开始 ART 的时间。
