This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mononuclear phagocytes (MP; microglia, perivascular and brain macrophages) are the predominant human immunodeficiency virus (HM infected cells in the brain. Circulating monocytes may serve to disseminate virus into brain and provide an ongoing source of neurotoxins from the periphery to the central nervous system (CNS). Indeed, the level of neurological impairment in HIV?associated dementia (HAD) correlates most with the numbers of activated MP, rather than the absolute levels of virus in brain tissue. Moreover, it has recently been shown that an immune competent monocyte subset emerges in blood coincident with the development of cognitive dysfunction. However, what triggers peripheral immune response(s) and its relationship to specific viral variants that affect CNS disease is now known. To these ends, we will test the relationships between peripheral monocyte activation and the emergence of specific viral variants to the development of cognitive impairment in a unique cohort of women with or at risk of dementia associated with HIV-1 infection. A group of 30 HIV positive patients with mild dementia (MSK of 1), 30 without dementia (MSK of 0) and 30 virus seronegative controls will be followed over a period of two years. In vivo signs of monocyte activation will be determined prospectively, in plasma and CSF, and include measures of soluble C014 (sCD14) sCD16 tumor necrosis factor receptor-2 (TNFR-2), macrophage chemotactic protein-I (MCP?1) and cell surface and/or intracellular measurements of CD14 and CD16, CD69, CCR5, CXCR4, OTK18, CD40 and CD40 ligand. Such results will be evaluated in the context of cognitive impairments by neurological examination, neuropsychological and magnetic resonance imaging tests. The relationship(s) if any between monocyte activation, neurotoxic responses and viral infection will be evaluated in laboratory studies. Here, monocytes, from demented, nondemented and control patients, will be cultivated in vitro. The differentiated cells will then be tested for the constitutive secretion of proinflammatory cytokines (TNF alpha, TNF-a, interleukin-one beta (IL-10) and chemokines (MCIP-1, macrophage inflammatory protein-1 alpha/beta (MIP-1a/b) and after immune activation with interferon gamma and IL-1 b or TNF-a (as would occur in an infected human host). Viral isolates obtained, in select patients, 5 from each of the groups, will be evaluated for co-receptor usage (CXCR4, CCR3 and CCRS) and provide unique profiling of HIV strains. The long-term goal of the project is to determine the relative role of viral and MP immune factor(s) that affect neural injury and cognitive decline during HIV infection.
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