AIDS is associated with a marked cognitive and motor dysfunction, termed HIV-associated dementia, in up to 20% of individuals. The introduction of potent combination antiretroviral therapy has reduced deaths from AIDS, and improved immunodeficiency in many. However, the impact of these therapies on neurological disease has only been studied to a limited extent; and the incidence and progression of dementia among injection drug users remains uncertain. Less severe cognitive impairment, termed minor HIV-associated cognitive/motor disorder has been less extensively studied and its prognosis and progression remain undefined. The progression of HIV-associated dementia can be variable, and some patients have rapid progression after diagnosis of dementia. The determinants of this variability remain unknown, but if defined, might be modified to affect disease progression. The relationship between HIV-1 viral load in the peripheral compartment and the brain has not been explored with currently available sensitive assays of viral load. A number of critical questions relating to viral load remain unanswered. First, does increasing systemic viral burden in the later stages of HIV infection """"""""drive"""""""" the development of neurologic disease. Second, is the amount of virus in the CSF reflective of virus production in the brain, or in the periphery?, and does it changes with antiretroviral therapy?. Finally, how is CNS immune activation, which is a critical component of CNS pathophysiology, related to blood and CSF viral load. We plan a systematic evaluation of virological and immunological markers in CSF in patients with HIV-associated cognitive/motor dysfunction to determine their utility as predictive markers for neurological disease progression. We have the following aims: 1) to determine the prognostic significance of CSF levels of HIV-1 RNA copy number for neurologic progression in a cohort of HIV-seropositive individuals; 2) to determine the dynamics of changes in HIV-1 RNA levels in plasma and CSF after initiation of combination antiretroviral therapy; 3) to determine the relationship between HIV RNA copy number in brain, plasma, and CSF and markers of immune activation. IF CSF HIV load measurement is validated as a predictive marker of neurological progression, individuals at high risk for neurological deterioration could be selected for aggressive neurologically-directed therapies.
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