The Hawaii AIDS Clinical Research Program (HACRP) has established a cohort of HIV-1 -infected individuals in Bangkok, Thailand to elucidate the mechanisms that induce HIV-1 associated dementia (HAD) in anti-retroviral naive individuals. This application will particularly focus on the role of cellular immune responses in the development of HAD using an expanded cohort of newly enrolled individuals and the established resources. This application is timely because The Thai Ministry of Public Health plans to provide anti-retroviral treatment for all HI V-1-infected individuals according to WHO guidelines. Thus, the opportunity to observe and study HAD before and after anti-retroviral therapy (ARV) within the same individual makes this cohort unique and invaluable. Moreover in contrast to most HIV-1 cohorts established in the US, the enrolled group will comprise of individuals with little to no exposure to illicit drugs, no hepatitis C exposure, and all starting the same ARVs. Therefore, fewer confounding factors exist to impact the HAD diagnosis. Increasing evidence links strong CD4+ T helper function with robust CD8+ CTL responses. HIV-1 - infected individuals who are able to maintain strong HIV-1 specific T cell responses have better clinical outcomes and rarely develop neurological symptoms. Monocyte/macrophage (M/M) infiltration into the white matter of the brain is a hallmark of HAD; yet the mechanisms by which these M/M are recruited to the brain are not clearly understood. We hypothesize that the loss of specific HIV-1 T cell responses results in activation/dysregulation of M/M leading to their accumulation in the brain. The mechanisms pertinent to this loss include: 1) the appearance of viral escape mutants that are no longer recognized by the T cells and 2) the loss of HIV specific CD4+ T cells by viral infection and cytolysis, both of which could results in increased blood M/M activation and infection and the development of HAD. To test this hypothesis we propose to enroll 20 HAD, 20 non-HAD, and 20 seronegative controls to be followed prospectively with neuropsychological data to: 1) define CD4+ and CDS T cell functions specifically by studying HIV-1 specific responses in HAD versus non-HAD individuals; 2) correlate these responses simultaneously with M/M subpopulation cell number, percentage and immune function; 3) correlate these responses with HIV-1 proviral load; and autologous viral sequences (viral escape sequences and HIV quasispecies) 4) correlate the impact of ARV on dementia with changes in immunological responses. The work described in this project will provide new insights into HIV-1 neuropathogenesis and its relationship to peripheral immune responses, thus opening exciting new areas for further investigation. The setting of this study in South East Asia will also provide novel information on how immunological responses correlate with HIV associated dementia in a population that is just starting anti retroviral drugs and is infected with clade E virus. ? ? ?
