Benlarbi Mehdi, Richard Jonathan, Clemente Tommaso, Bourassa Catherine, Tolbert William D, Gottumukkala Suneetha, Messier-Peet Marc, Medjahed Halima, Pazgier Marzena, Maldarelli Frank, Castagna Antonella, Durand Madeleine, Finzi Andrés
Centre de Recherche du CHUM, Montréal, QC, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC, Canada.
Vita-Salute San Raffaele University, Milan, Italy; Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
EBioMedicine. 2025 Jul 19;118:105856. doi: 10.1016/j.ebiom.2025.105856.
While antiretroviral therapy (ART) efficiently suppresses viral replication, inflammation and immune dysfunction persist in some people living with HIV-1 (PLWH). HIV-1 soluble gp120 (sgp120) has been detected in PLWH plasma and its presence is linked to immune dysfunction. It was reported that sgp120 binding to CD4 on uninfected bystander CD4 T cells sensitises them to cellular death via antibody-dependent cellular cytotoxicity (ADCC) mediated by non-neutralising anti-cluster A antibodies (Abs) present in PLWH plasma.
We included plasma from 520 PLWH on ART from three independent cohorts for measurements of anti-cluster A Abs and anti-CD4 binding site (anti-CD4BS) Abs. Associations between CD4 T cell counts and anti-cluster A Abs was assessed using generalised least squares linear regression models, adjusting for potential confounders including age, sex, nadir CD4 and duration of ART. The role of anti-CD4BS Abs was evaluated using flow-cytometry based ADCC assays with primary CD4 T cells.
We observed that non-neutralising anti-cluster A Abs are negatively associated with CD4 T cell counts. Anti-CD4BS antibodies blocked the coating of uninfected bystander cells by sgp120, thereby preventing their elimination by ADCC. Supporting a protective role of anti-CD4BS antibodies, their presence in PLWH plasma abrogated the negative association between CD4 counts and anti-cluster A Abs.
Our results reveal that anti-cluster A Abs are associated with immune dysfunction in PLWH and anti-CD4BS antibodies might have a beneficial impact in these individuals.
This study was supported by the Canadian Institutes of Health Research, the Canada Foundation for Innovation, the Fonds de Recherche du Québec-Santé, and the National Institutes of Health.
虽然抗逆转录病毒疗法（ART）能有效抑制病毒复制，但一些HIV-1感染者（PLWH）仍存在炎症和免疫功能障碍。在PLWH血浆中已检测到HIV-1可溶性糖蛋白120（sgp120），其存在与免疫功能障碍有关。据报道，sgp120与未感染的旁观者CD4 T细胞上的CD4结合，通过PLWH血浆中存在的非中和性抗A簇抗体（Abs）介导的抗体依赖性细胞毒性（ADCC）使这些细胞对细胞死亡敏感。
我们纳入了来自三个独立队列的520名接受ART治疗的PLWH的血浆，用于检测抗A簇抗体和抗CD4结合位点（抗CD4BS）抗体。使用广义最小二乘线性回归模型评估CD4 T细胞计数与抗A簇抗体之间的关联，并对包括年龄、性别、最低CD4值和ART持续时间在内的潜在混杂因素进行调整。使用基于流式细胞术的ADCC试验，用原代CD4 T细胞评估抗CD4BS抗体的作用。
我们观察到非中和性抗A簇抗体与CD4 T细胞计数呈负相关。抗CD4BS抗体可阻止sgp120对未感染的旁观者细胞的包被，从而防止其被ADCC清除。抗CD4BS抗体在PLWH血浆中的存在消除了CD4计数与抗A簇抗体之间的负相关，支持了抗CD4BS抗体的保护作用。
我们的结果表明，抗A簇抗体与PLWH的免疫功能障碍有关，而抗CD4BS抗体可能对这些个体有有益影响。
本研究得到了加拿大卫生研究院、加拿大创新基金会、魁北克卫生研究基金和美国国立卫生研究院的支持。
