In HIV infection, circulating CD4+ T cell counts predict disease progression. Even under long-term suppressive antiretroviral therapy (ART), up to 25% of virologically suppressed people living with HIV (PLWH) fail to restore CD4+ T cell counts to the levels similar to those in healthy controls, and increased morbidity and mortality have been demonstrated in these immune non-responders. We were the first group to report that anti-CD4 IgGs mediate CD4+ T cell death and play a role in poor immune recovery under ART. While the pathogenesis is likely multifactorial, such as thymic and lymphatic fibrosis, systemic immune activation, and inflammation, our proposed pathologic anti-CD4 IgG-mediated CD4+ T cell depletion provides a unique mechanism for targeting CD4+ T cells specifically. In the current study, we will investigate the molecular mechanisms of pathologic anti- CD4 IgGs and anti-CD4 autoreactive B cells from immune non-responders and identify the therapeutic targets to prevent anti-CD4 IgG-mediated pathogenesis together with traditional ART to increase immune recovery and reduce complications, morbidity and mortality in HIV+ Veterans and non-Veterans. AIM 1. Determine the pathologic activities of anti-CD4 IgGs on CD4+ T cell activation and function and HIV latency through the CD4 receptor signaling pathway in HIV+ immune non-responders. AIM 2. Determine the B cell receptor characteristics and gene expression landscape of anti-CD4 autoantibody- producing B cells from HIV+ immune non-responders. AIM 3. Determine the biochemical properties and shared antigen binding epitopes of pathologic anti-CD4 monoclonal IgGs in HIV+ immune non-responders. This line of investigation possesses great therapeutic potential for Veteran and non-Veteran HIV-positive individuals presenting with poor CD4+ T cell recovery, a population with particularly high risk for morbidity and mortality and thus an area of public health importance.