On the pathogenic role of anti-CD4 antibody in poor CD4+ T cell recovery after antiretroviral therapy in HIV disease

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Human immunodeficiency virus (HIV) disease has been significantly controlled following the introduction of antiretroviral therapy (ART) [1]. This treatment dramatically improves immune function, suppresses HIV viral replication, and decreases morbidity and mortality [1, 2]. However, up to 25% of virologically suppressed individuals (~111,000 people in USA) fail to restore their CD4+ T cells to counts > 350 cells/µL, even after long- term ART treatment and viral suppression [3], and increased morbidity and mortality have been observed in these patients [4-7]. Thymic fibrosis has been suggested a mechanism, and low nadir CD4+ T cell counts and T cell activation have been shown to associate with incomplete immune restoration after ART treatment [8-11], but mechanisms for immune non-response remain largely unknown. To better understand mechanisms of incomplete immune restoration, we performed a preliminary human study in 12 healthy controls, 17 immunologic responders (IRs) (aviremic and ART treated > 3 years, and CD4+ T cell counts > 500 cells/µL) and 11 immunologic non-responders (INRs) (aviremic and ART treated > 3 years, and CD4+ T cell counts < 350 cells/µL) [8]. Elevated plasma levels of anti-CD4 IgGs were found in patients compared to controls and correlated with blunted CD4+ T cell recovery. Furthermore, purified anti-CD4 IgGs from plasma of aviremic long-term ART-treated subjects with CD4+ T cell counts below 350 cells/µl, defined as “immunologic non- responders”, induced antibody-dependent NK cell-mediated cytotoxicity against CD4+ T cells. We hypothesize that heightened level of anti-CD4 Ab contributes to the pathogenesis of CD4+ T cell losses in HIV infection. If our hypothesis is correct, a therapeutic strategy that targeting autoreactive B cells or anti-CD4 Abs could potentially optimize ART treatment to improve CD4+ T cell recovery and reduce mortality and morbidity in treated HIV-infected patients. This study will also provide important information in HIV vaccine design.