PLA2G1B is involved in CD4 anergy and CD4 lymphopenia in HIV-infected patients
Julien Pothlichet, … , Gérard Lambeau, Jacques Thèze
Julien Pothlichet, … , Gérard Lambeau, Jacques Thèze
Published March 3, 2020
Citation Information: J Clin Invest. 2020;130(6):2872-2887. https://doi.org/10.1172/JCI131842.
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Research Article AIDS/HIV Immunology

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

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+ 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.

Authors

Julien Pothlichet, Thierry Rose, Florence Bugault, Louise Jeammet, Annalisa Meola, Ahmed Haouz, Frederick Saul, David Geny, José Alcami, Ezequiel Ruiz-Mateos, Luc Teyton, Gérard Lambeau, Jacques Thèze

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Figure 4

Cloned plasma PLA2G1B induces the Bumpy T cell phenotype.

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Cloned plasma PLA2G1B induces the Bumpy T cell phenotype. (A) Crystal st...
(A) Crystal structure of PLA2G1B (PDB: 6Q42). (B) PLA2G1B effect on MMD formation followed by STED (representative of 2 experiments at 250 nM and verified at 500 nM and 1 μM). (C) Dose effect of PLA2G1B on IL-7–induced p-STAT5 NT in HD purified CD4+ T cells after analysis of confocal images. Results are shown as the mean ± SD from 4 donors. (D–G) The effects on aMMD formation (D and E) and p-STAT5 NT (F and G) in CD4+ T cells of 250 nM WT PLA2G1B were compared to those of the inactive mutant H48Q (D and F) and other PLA2s (PLA2GIIA, PLA2GIID, or PLA2GX) (E and G). Results are shown as the mean ± SD from 5 (D–F) or 7 donors (G). (H) VP plasma (3%, from 5 donors) was depleted with anti-PLA2G1B, anti-PLA2GIIA, or anti-PLA2GIID rabbit polyclonal antibodies (100 μg/mL). The effect of depletion was analyzed by following p-STAT5 NT in IL-7–stimulated CD4+ T cells (n = 3 donors) incubated with depleted plasma. Results were normalized to the response obtained with HD plasma and are shown as the mean ± SD. (I) Effect of VP plasma treated with various doses of neutralizing anti-PLA2G1B mAb 14G9 on p-STAT5 NT in CD4+ T cells from 1 donor and the effect of 100 μg/mL of 14G9 mAb on p-STAT5 NT in CD4+ T cells from 5 donors. **P < 0.01; ***P < 0.001 by Mann-Whitney t test (D, F, and I) and by the Kruskal-Wallis test followed by the Mann-Whitney test with P values adjusted for multiple comparisons between groups (E and G) or 1-way ANOVA (H) with Tukey’s correction for multiple comparisons.