Moysi Eirini, Sharma Ashish A, O'Dell Sijy, Georgakis Spiros, Del Rio Estrada Perla Mariana, Torres-Ruiz Fernanda, Navarro Mauricio González, Villalobos Yara Andrea Luna, Rios Santiago Avila, Reyes-Teran Gustavo, Beddall Margaret H, Ko Sung-Hee, Belinky Frida, Orfanakis Michail, de Leval Laurence, Enriquez Ana B, Buckner Clarisa M, Moir Susan, Doria-Rose Nicole, Boritz Eli, Mascola John R, Sekaly Rafick-Pierre, Koup Richard A, Petrovas Constantinos
Tissue Analysis Core, Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, MD, USA.
Pathology Advanced Translational Research Unit, Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.
bioRxiv. 2024 Aug 3:2024.07.31.605954. doi: 10.1101/2024.07.31.605954.
A subset of people living with HIV (PLWH) can produce broadly neutralizing antibodies (bNAbs) against HIV, but the lymph node (LN) dynamics that promote the generation of these antibodies are poorly understood. Here, we explored LN-associated histological, immunological, and virological mechanisms of bNAb generation in a cohort of anti-retroviral therapy (ART)-naïve PLWH. We found that participants who produce bNAbs, termed neutralizers, have a superior LN-associated B cell follicle architecture compared with PLWH who do not. The latter was associated with a significantly higher prevalence of Bcl-6 follicular helper CD4 T cells (TFH), expressing a molecular program that favors their differentiation and stemness, and significantly reduced IL-10 follicular suppressor CD4 T cells. Furthermore, our data reveal possible molecular targets mediating TFH- B cell interactions in neutralizers. Together, we identify cellular and molecular mechanisms that contribute to the development of bNAbs in PLWH.
一部分感染艾滋病毒的人（PLWH）能够产生针对艾滋病毒的广泛中和抗体（bNAb），但促进这些抗体产生的淋巴结（LN）动态变化却知之甚少。在此，我们在一组未接受抗逆转录病毒治疗（ART）的PLWH队列中，探究了与LN相关的bNAb产生的组织学、免疫学和病毒学机制。我们发现，能够产生bNAb的参与者（称为中和者）与不能产生bNAb的PLWH相比，具有更优质的与LN相关的B细胞滤泡结构。后者与Bcl-6滤泡辅助性CD4 T细胞（TFH）的显著更高患病率相关，这些细胞表达有利于其分化和干性的分子程序，并且IL-10滤泡抑制性CD4 T细胞显著减少。此外，我们的数据揭示了中和者中介导TFH与B细胞相互作用的可能分子靶点。我们共同确定了有助于PLWH中bNAb产生的细胞和分子机制。
