Although it is clear that CD4+ monocytes can be infected with HIV1 and that cells of the monocyte/macrophage series are prominent among the HIV1-infected cells in the central nervous system (CNS), there is considerably less agreement about how infection with HIV1 influences function of monocytes. There is little or no information about influences which affect the entry of HIV1-infected monocytes into the CNS, and other extravascular sites. This proposal brings together 4 groups of investigators with expertise in immunology, virology, the biology of leukocytes and psychiatry/psychology to comprehensively evaluate alterations of monocyte/macrophage function following HIV1 infection, with the specific aim of studying how infection with this virus affects the ability of these cells to adhere to and penetrate vascular endothelium, and carry out other functions of """"""""activated"""""""" monocytes. Basic studies of HIV1-infected monocyte behavior will be carried out in tandem with clinical investigations in which HIV1-infected patients will be followed longitudinally for the development of cognitive dysfunction or other symptomatology associated with HIV1 involvement of the CNS. These investigations will test the hypothesis that patients who develop CNS symptomatology have a significantly greater burden of HIV1- infected circulating monocytes, and that measurement of the quantity of HIV1 in the monocytes may be useful, prognostically. To estimate the quantity of HIV1 in peripheral blood monocytes, these cells will be isolated and analyzed for HIV1 by in situ hybridization with an ARV-2 DNA probe. RNA will also be analyzed by nucleic acid hybridization and the polymerase chain reaction (PCR) will be applied to DNA extracts of these cells to amplify and detect constant region sequences of HIV1 DNA. Expression of molecules of the CD 11/CD 18 complex and ICAM-1 which facilitate monocyte adherence and penetration of vascular endothelial barriers will be measured by flow cytometry and correlated with the ability of these cells to react with and penetrate cultured endothelial cell monolayers, and to carry out other functions of normal monocytes, including responsivity to chemotactic stimuli, phagocytosis and intracellular killing, secretion of cytokines and release of proteolytic enzymes. Results of studies of subpopulations of peripheral blood monocytes, isolated by cell sorter, and characterized by flow cytometric analysis, will be compared to results of functional and cell surface marker studies of U937 and THP1 promonocytic cells in which the proportion of HIV1 infected cells has been carefully controlled by mixing in known quantities of uninfected pro-monocytic cells. We postulate that these studies will better define the impact of HIV1 infection on monocyte function and illuminate mechanisms by which such cells enter the CNS and other tissue sites.

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National Institute of Allergy and Infectious Diseases (NIAID)
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Baylor College of Medicine
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