HIV associated CNS disorders represent a major health problem in a significant proportion of HIV infected individuals. These disorders include minor cognitive and motor disorders, HIV dementia, as well as peripheral neuropathy. The neurologic complications of AIDS develop, in part, because of the invasion of macrophages derived from peripheral blood into the central and peripheral nervous system tissues. Our previous studies have identified the accumulation of a monocyte subset (CD14+/CD163+/CD16+) in peripheral blood in patients with HIV infection and SIV infected rhesus macaques. These monocytes in circulation appear to represent precursors of the perivascular macrophages accumulating in HIV/SIV encephalitis. Normally low in healthy individuals, this subset appears to expand to a degree correlating with HIV/SIV plasma viral load, and inversely with CD4+ T cell count. Based on the phenotype of these cells, the immunosuppression observed in AIDS, together with new information regarding the phenotype and function of distinct monocyte/macrophages subsets, we propose that CD14+/CD163+/CD16+ monocytes accumulating in AIDS, play a role in immune polarization and may contribute to the immunopathogenesis of AIDS. In the studies proposed in this application, we will utilize the SIV infected rhesus macaque model to study the consequences of SIV infection in altering monocyte/macrophage dynamics using the simultaneous combination of two in vivo cell tracking approaches. An approach utilizing CFSE fluorescent dye and BrdU labeling will be employed to study monocyte/macrophage dynamics in SIV infected, SIV infected/CD8+ T cell depleted, and healthy control animals. In order to identify potential effects solely attributable to the CD8+ T cell depletion and to further understand normal homeostatic processes, uninfected CD8+ T cell depleted animals will also be studied. We will further determine if the CD14+/CD163+/CD16+ monocyte exhibits immune polarization using antigen specific immune assays and the characterization of cytokines, chemokines as well as regulatory pathways using multiplex (Luminex) and Affymetrix gene chip approaches. The studies proposed here may provide new avenues for investigation and the development of therapies targeting the monocyte/macrophage in AIDS and NeuroAIDS.
HIV infection is major problem worldwide. The monocyte/ macrophage system not only provides a stable reservoir for the virus, but these cells are responsible for trafficking of HIV into the CNS and other tissues. The studies proposed here may have a major impact on our understanding of the function of the monocyte/macrophage in the development of CNS disease, and at the same time investigate their role in contributing to immune dysfunction in AIDS.
