1. PLA2G1B is involved in CD4 anergy and CD4 lymphopenia in HIV-infected patients
- Author
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Pothlichet, Julien, Rose, Thierry, Bugault, Florence, Jeammet, Louise, Meola, Annalisa, Haouz, Ahmed, Saul, Frederick, Geny, David, Alcami, Jose, Ruiz-Mateos, Ezequiel, Teyton, Luc, Lambeau, Gerard, and Theze, Jacques
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HIV patients -- Physiological aspects ,HIV infections -- Physiological aspects ,Lymphocytopenia -- Physiological aspects ,HIV -- Physiological aspects ,Immunotherapy -- Physiological aspects ,T cells -- Physiological aspects ,Health care industry - Abstract
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.sup.+] 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.sup.+] T cell surface. The PLA2G1B/gp41 pair induced [CD4.sup.+] 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.sup.+] T cells. PLA2G1B also decreased [CD4.sup.+] 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.sup.+] 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., Introduction [CD4.sup.+] lymphocytes play a critical role in the severe immunodeficiency that characterizes HIV-infected patients. Although fewer than 0.5% of blood [CD4.sup.+] T cells are infected, almost all are dysfunctional. [...]
- Published
- 2020
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