PLA2G1B is involved in CD4 anergy and CD4 lymphopenia in HIV-infected patients.

The precise mechanism leading to profound immunodeficiency of HIV-infected patients is still only partially understood. Here, we show that more than 80% of CD4+ T cells from HIV-infected patients have morphological abnormalities. Their membranes exhibited numerous large abnormal membrane microdomains (aMMDs), which trap and inactivate physiological receptors, such as that for IL-7. In patient plasma, we identified phospholipase A2 group IB (PLA2G1B) as the key molecule responsible for the formation of aMMDs. At physiological concentrations, PLA2G1B synergized with the HIV gp41 envelope protein, which appears to be a driver that targets PLA2G1B to the CD4+ T cell surface. The PLA2G1B/gp41 pair induced CD4+ T cell unresponsiveness (anergy). At high concentrations in vitro, PLA2G1B acted alone, independently of gp41, and inhibited the IL-2, IL-4, and IL-7 responses, as well as TCR-mediated activation and proliferation, of CD4+ T cells. PLA2G1B also decreased CD4+ T cell survival in vitro, likely playing a role in CD4 lymphopenia in conjunction with its induced IL-7 receptor defects. The effects on CD4+ T cell anergy could be blocked by a PLA2G1B-specific neutralizing mAb in vitro and in vivo. The PLA2G1B/gp41 pair constitutes what we believe is a new mechanism of immune dysfunction and a compelling target for boosting immune responses in HIV-infected patients.This work was part of the ANRS programs EP20, EP33, and EP36 (J.F. Delfraissy, O. Lambotte). It was initially supported by the Institut Pasteur (PTR 424) and the Pasteur-Weizmann Foundation. We are grateful to P. Pouletty for continuous interest and support. We wish to thank U. Schwarz (Leica Microsystems, Mannheim), E. Perret, P. Roux, A. Salles, and S. Shorte (Imagopole, Institut Pasteur) for their microscopy expertise, as well as A.H. Pillet for her expertise in biochemistry and P. Bochet for data processing and Benoit Colsch (Laboratoire d’Etude du Métabolisme des Médicaments (LEMM), CEA, INRA, Université Paris Saclay, MetaboHUB) for lipidomics analysis by mass spectrometry of CD4+ and CD8+ T cells. We thank Yoann Madec and Fredj Tekaia for their help and expertise in statistics. We acknowledge SOLEIL for the provision of synchrotron radiation facilities and thank the staff of the PROXIMA-1 beamline for their assistance. We benefited greatly from help and numerous discussions with C. Abrial, L. Touqui, B. Colsch, D. Troisvallet, M.L. Gougeon, P. Bruhns, and J. Tiollier. We also gratefully acknowledge J.P. Routy and B. Malissen for their critical review of the manuscript.S