Anti-CD4 autoantibody-mediated failure of CD4+ T cell reconstitution in HIV-infected patients under viral-suppressive ART

Abstract

Abstract Increased mortality and morbidity occur in HIV-infected patients who fail to increase CD4+ T cell counts under viral-suppressive antiretroviral therapy (ART). Here we identified an underlying mechanism. Plasma anti-CD4 IgGs were measured by ELISA in 17 healthy controls, 26 HIV+ immunologic responders (IR, aviremic, CD4+ T cell counts ≥ 500 cells/μL), and 22 non-responders (NR, aviremic, CD4+ T cell counts < 350 cells/μL). Anti-CD4 IgGs were purified from plasma of 21 NR by affinity purification. Antibody-dependent cytotoxicity (ADCC) was performed in CD4+ T cells co-cultured with NK cells in presence of anti-CD4 IgGs or control IgGs in vitro. Plasma microbiome was analyzed by bacterial 16S DNA sequencing. Elevated plasma levels of anti-CD4 IgGs were found in NR [median (interquartile range, ng/mL), 92 (53–166)] compared to IR [26 (16–82)] and healthy controls [16 ng/mL (9–24)] (P < 0.001 between NR and two controls, ANOVA). Higher plasma level of anti-CD4 IgG correlated with blunted CD4+ T cell recovery (r = −0.53, P = 0.0002, Spearman correlation test). Furthermore, purified anti-CD4 IgGs induced NK cell-dependent CD4+ T cell cytolysis (P = 0.02). Notably, Simpson diversity was lower in patients with plasma anti-CD4 IgG ≥ 50 ng/mL compared to patients with anti-CD4 IgG < 50 ng/mL (P = 0.04). There was an inverse correlation between plasma anti-CD4 IgG and the Simpson diversity index in patients (r = −0.47, P = 0.03) but not in healthy controls. These results indicate a possible link between microbiome and B cell dysfunction in HIV, and anti-CD4 IgGs may play an important role in preventing CD4+ T cell reconstitution despite viral-suppressive ART.