Investigate B cell perturbations and immune reconstitution failure in response to antiretroviral therapy in HIV-infected cocaine users

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PROJECT SUMMARY/ABSTRACT In HIV infection, circulating CD4+ T cell counts predict disease progression. Among infected subjects, up to 25% of antiretroviral therapy (ART)-treated people with HIV (PWH) (~111,000 people) fail to restore their peripheral CD4+ T cell counts to the levels of healthy controls, and increased morbidity and mortality have been demonstrated in these patients with immune reconstitution failure. Substance use disorders are common among people who are HIV infected, and drug of abuse is associated with poor CD4+ T cell recovery in patients on viral- suppressive ART. In this study, we will investigate how cocaine impacts on autoreactive B cell functions. We are the first group to report that anti-CD4 autoantibodies mediate CD4+ T cell death via antibody-mediated cytotoxicity (ADCC) and contribute to poor CD4+ T cell recovery under suppressive ART. Previous studies indicate that cocaine or levamisole-tainted cocaine (69% of cocaine is contaminated with levamisole) is able to induce autoantibodies and clinical presentations of autoimmune diseases. Thus, we hypothesize that cocaine or levamisole-tainted cocaine activates autoreactive B cells and promotes anti-CD4 autoantibody production in PWH. Our goal is to improve CD4+ T cell recovery and reduce mortality and morbidity in HIV+ cocaine users on suppressive ART. AIM 1: Determine the association of levamisole-tainted cocaine use and plasma anti-CD4 IgG levels in HIV+ cocaine users on suppressive ART. AIM 2: Characterize anti-CD4 IgG-producing single B cell gene “signature” in HIV+ levamisole-tainted cocaine users on suppressive ART.