Neutralization activity in chronic HIV infection is characterized by a distinct programming of follicular helper CD4 T cells

Eirini Moysi; Ashish A. Sharma; Sijy J. O'Dell; Spiros Georgakis; Perla Mariana Del Rio Estrada; Khader Ghneim; Alonso Arana; Fernanda Torres-Ruiz; Mauricio González-Navarro; Yara Andrea Luna-Villalobos; Santiago Ríos; Gustavo Reyes‐Terán; Margaret H. Beddall; Sung Hee Ko; Frida Belinky; Michail Orfanakis; Laurence de Leval; Ana Beatriz Enriquez; Clarisa M. Buckner; Susan L. Moir; Helen Lindsay; Raphaël Gottardo; Nicole A. Doria-Rose; Eli Boritz; John R. Mascola; Rafick‐Pierre Sékaly; Richard A. Koup; Constantinos Petrovas

doi:10.1172/jci192575

ImmunologyJournal of Clinical InvestigationJul 14, 2026

Peer-reviewed journal article

Neutralization activity in chronic HIV infection is characterized by a distinct programming of follicular helper CD4 T cells

Eirini Moysi iD, Ashish A. Sharma iD, Sijy J. O'Dell iD, Spiros Georgakis iD, Perla Mariana Del Rio Estrada iD, Khader Ghneim iD, Alonso Arana, Fernanda Torres-Ruiz iD, Mauricio González-Navarro iD, Yara Andrea Luna-Villalobos, Santiago Ríos, Gustavo Reyes‐Terán iD, Margaret H. Beddall iD, Sung Hee Ko iD, Frida Belinky iD, Michail Orfanakis iD, Laurence de Leval iD, Ana Beatriz Enriquez iD, Clarisa M. Buckner iD, Susan L. Moir iD, Helen Lindsay, Raphaël Gottardo iD, Nicole A. Doria-Rose iD, Eli Boritz iD, John R. Mascola iD, , Constantinos Petrovas iD

Abstract

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)-naive 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 in situ prevalence of Bcl-6hi 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.

PDF DOI