DESCRIPTION (provided by applicant): The prevalence of HIV-associated neurocognitive disorders (HAND) has increased owing to the widespread use of combined antiretroviral treatment (cART) and resulting longer survival of HIV-infected patients. Among HIV-seropositive patients on cART, most suffer from the milder forms of HAND. Recently, blood sugar metabolism abnormalities have been identified in HIV-infected individuals and associated with HAND. Retrospective data from our cohort showed that exosomes from HIV-seropositive women on cART contain high levels of sIR as well as HIV-1 Tat, and that exosomal levels of both sIR and HIV-1 Tat are associated with the presence and severity of HAND in these women. Our long-term goal is to identify novel mechanisms to explain the pathogenic process of insulin resistance and cognitive impairment in HIV-seropositive population. The rationale for the current study lies with previous observations by our lab and others that blood sugar metabolism abnormalities are associated with HAND. Our central hypothesis is that elevated levels of plasma exosomal sIR and PBMCs SF2-ASF/hnRNPA1 ratio contribute to high levels of plasma sIR and the development and progression of HAND. The objective of this study is to examine the relationship of sIR plasma levels, exosomal sIR levels, SF2-ASF/hnRNPA1 ratio levels, insulin resistance, and HAND in a cohort of HIV-seropositive patients on cART. We propose the following AIMs: 1. To determine if sIR and HIV-1 Tat levels in plasma exosomes are associated with HAND, 2. To determine if the SF2-ASF/hnRNPA1 splicing factors ratio is associated with HAND and correlates with the levels of exosomal sIR, and 3. To determine the influence of gender differences in the levels of plasma exosomal sIR and HIV-1 Tat and PBMCs SF2- ASF/hnRNPA1 ratio of HIV-seropositive participants with HAND. We expect an association between plasma sIR levels, exosomal sIR and HIV-1 Tat, SF2-ASF/hnRNPA1 ratio levels, insulin resistance, and HAND in a cohort of HIV-seropositive women using cART. This is a novel study for the detection of exosomal sIR and HIV-1 Tat and the identification of the mechanisms responsible for the secretion of sIR-full length to the plasma of HIV-seropositive patients. It is significant since the identification of these molecular mechanisms in the neuropathophysiology of HAND could serve to design novel approaches and treatment regimens for the prevention and treatment of insulin resistance and cognitive impairment in HIV-seropositive patients.