The prevalence of HAD has not changed in the era of HAART, nor has the rate of HIV-1 encephalitis. HAART has provided suboptimal improvement in HIV-1-related cognitive deficits. Monocyte/macrophage (M/Mphi) activation products may underlie this incomplete recovery. A reduction in M/Mphi activation markers has never been demonstrated in a longitudinal cohort and the extent to which incomplete resolution of M/Mcp activation post-HAART contributes to incomplete cognitive recovery is not known. We hypothesize that while M/M/phi activation is decreased with HAART, a degree of activation persists in some individuals and the degree of attenuation in M/M/phi activation relates to the degree of improvement on neuropsychological testing. We believe that one of the underlying mechanisms responsible for the residual macrophage activation involves continued HIV-1 infection in sequestered reservoirs, particularly within macrophages themselves. To test our hypotheses, we plan to quantify intracellular HIV-1 DNA copy number and measure M/M/phi activation markers at baseline and 6, 12, and 24 months after initiation of HAART in a cohort of HAD patients in Bangkok, Thailand as they initiate their first HAART regimen and compare these to non-HAD patients and HIV-negative controls. If our hypotheses are correct, we expect to see residual infection in M/M/phi's, particularly within CD14+/CD16+ cells, indicating a relationship between M/M/phi activation and intracellular infection. We further expect to see a time-relationship between treatment duration and percent activation. Finally, we expect to see a direct relationship between the decrease in activation and the improvement on neuropsychological testing. Given this unique cohort, we further intend to use proteomics to generate important molecular markers that predict M/M/phi response to HAART and that distinguish HAD in HAART-treated compared to HAART-naive individuals.
