Natural killer (NK) and activated NK (LAK) cells are considered to be of importance in host defense against a variety of viral infections. However, little is known about the role of NK cells in response to human immunodeficiency virus (HIV) infection. Numerous investigators have shown that, using standard tumor cell targets, NK activity is depressed during HIV infection. We have reported that CD16+ blood cells can preferentially lyse HIV-infected promonocytic cells (U937HIV) as compared with uninfected U937 .cell targets. This is associated with production of alpha interferon (aIFN) in the effector-target cultures, which in turn is related to an HLA-DR+ light density accessory .cell. We propose to combine the resources of the research groups of Drs. Rinaldo, Gupta, Herberman and Whiteside in Pittsburgh in a comprehensive investigation of NK and LAK cell response to HIV infection. We hypothesize that NK activity observed against HIV infected targets is due to a combination of CD3- NK cells and CD3+ T lymphocytes with MHC-unrestricted activity. These may differ in proportion and function during HIV infection. Therefore, we will further characterize the phenotype and function of effector cells responsible for lysis of HIV-infected targets by flow cytometric analysis and cell enrichment techniques. This will include effects of cytokines on augmenting NK activity in HIV-infected subjects, and analysis of NK cell specificity by cold-target inhibition studies. We postulate that the deficiency in NK cytotoxic function during HIV infection is primarily due to decreased ability of accessory cells to produce these cytokines. Hence, the role of accessory cells, in particular HLA-DR+ mononuclear cells, will be defined by similar enrichment methods, including studies of AIFN production and soluble lytic factors. Finally, we propose that the target structures on HIV infected cells that make them more susceptible to lysis by NK and LAK cells represent a combined upregulation of host-coded adhesion molecules, and possibly virus-coded proteins. Experiments are proposed to delineate the function of membrane adhesion molecules, specific HIV-coded gene products, and strains of HIV in augmented lysis of U937HIV cells. Similar studies will be done to characterize NK and LAK cell activity against HIV-infected peripheral blood monocyte-derived macrophages. These studies will be of importance in defining natural cell-mediated immunity to HIV, and in developing appropriate drug treatment protocols for HIV infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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AIDS and Related Research Study Section 1 (ARRA)
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University of Pittsburgh
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