Impacts of drug abuse-mediated inflammatory perturbations on affinity maturation of anti-CD4 autoantibodies and poor immune reconstitution from ART in HIV

ABSTRACT This resubmitted proposal is in response to RFA-DA-25-012 (reissue of RFA-DA-24-003) for “Antibody- mediated enhancement of HIV infection/replication following B-cell responses can result in depletion and blunted recovery of CD4+ T-cells and poor immune recovery despite suppressive ART. How these immune components in the context of HIV infection and substance use disorder contribute to the pathology of both conditions represents a significant knowledge gap. Studies focused on inflammasome cascades and pathogenic antibodies mediated by chronic drug use and HIV infection are warranted”. About 25% HIV patients under anti-retroviral therapy (ART) fail to recover CD4+ T cell counts to a level comparable to healthy people. Because CD4+ T cell is critical for immune response to foreign pathogens, it is critical to develop new medications to recover CD4+ T cell counts to reduce co-morbidity and mortality in HIV. Our preliminary studies reveal anti-CD4 autoantibodies to be increased in HIV+ drug abusers and to play a key role in inducing CD4+ T cell death. How cocaine (proinflammation) and cannabis (anti-inflammation) use affect B cell function, pathogenic anti-CD4 autoantibody development, and CD4+ T cell recovery from ART in PWH remains unclear, thus, we propose two aims here: Aim 1. Determine mechanisms of affinity maturation and CD4 recognition for anti-CD4 autoantibodies presenting ADCC activity in HIV+ drug users. Aim 2. Determine drug use-mediated B cell perturbations, anti-CD4 autoantibody production, and HIV immunopathogenesis.