Resistance of HIV-infected Cells to Natural Killer Cells

Upstate Medical University, Syracuse NY

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant):Natural killer (NK) cells play an important role in innate immune responses against viral pathogens by recognizing and destroying virus-infected cells. This response is especially important since HIV can decrease the expression of major histocompatibility complex (MHC) class I molecules in order to avoid recognition by CD8+ cytotoxic T-lymphocytes. However, decreasing the expression of MHC class I molecules makes the cells more vulnerable to NK cells since these cell surface molecules can inhibit NK cell-mediated responses. NK cells have the ability to lyze HIV-infected CD4+ cells lines but lack the capability to lyze autologous HIV-infected primary CD4+ cells even though primary CD4+ cells are susceptible to the lytic machinery of NK cells. The failure of NK cells to lyse HIV-infected primary cells may be due to the inability of the infected cells to trigger NK cell activation. For this purpose we will determine at which level in the activation process HIV prevents NK cells from lysing primary CD4+ cells infected with HIV. First we determine if NK cells are able to adhere to HIV-infected cells to the same extent as uninfected cells and more importantly determine if HIV alters the expression of adhesion molecules on infected cells. Second we will determine if HIV can alter the expression of ligands for natural cytotoxicity receptors on the infected cell surface. Finally we will determine whether HIV can leave select MHC class I molecules on the surface of primary CD4+ cells which can impede the ability of NK cells to mediate a cytotoxic response. Understanding the mechanism by which HIV-infected cells escape killing by NK cells will explain why very little immune control of HIV infection occurs prior to the appearance of adaptive immune responses during primary HIV infection.