Innate immunity is the first line of defense designed to protect the host from invading pathogens, including HIV. We have previously demonstrated that suppression of natural killer (NK) cell function can be profound and that it is related to the stage of HIV infection as well as the level of HIV plasma viremia. Our study revealed that HIV viremia impairs the ability of NK cells to secrete CC-chemokines and alters the expression of various inhibitory and chemokine receptors expressed on NK cells. Further analysis of NK-cell specific surface receptors revealed upregulation of inhibitory NK receptors and chemokine receptor CCR5. In addition, our data showed CCR5 upregulation to be induced as a result of immune activation while induction of iNKRs appeared to be a direct result of an HIV-induced effect. Analysis of NK cell interactions with R5 and X4 HIV envelopes showed profound suppression of generic NK cell function upon exposure to these envelopes. Furthermore, DNA microarray analyses of NK cells in the presence and absence of HIV envelopes delineated upregulation of several genes that were important in inducing apoptosis and suppression of cell proliferation. Similarly, exposure to HIV envelopes suppressed the expression of several genes critical for cell proliferation and generic NK cell function. Functional studies confirmed the profound suppresssive ability of HIV envelopes on generic NK cell functions such as cytotoxicity, proliferation, and secretion of cytokines and chemokines. Future studies will be focused on delineating the underlying mechanisms involved in the interaction between R5 and X4 HIV envelopes and NK cells. Further studies will address the cellular and molecular basis for this HIV envelope-induced suppressive effect on NK cells. Specific roles of NK cell receptors, particularly those belonging to the C-type lectin family will be investigated as potential igands for HIV envelopes. DNA microarray analyses of NK cells from HIV viremic patients showed upregulation of genes induced by interferon when compared with those from HIV aviremic individuals and HIV seronegative normal volunteers. Analyses of these gene clusters have lead us to identify pathways of signal transduction that are abnormally regulated in HIV viremic state. We have further demonstrated that NK cells from HIV viremic patients express relatively higher levels of fas molecule on their surface and are susceptible to fas-mediated apoptosis upon exposure to sFASL. In addition, NK cells from HIV viremic individuals have reduced surface expresssion of interleukin receptors and express significantly higher levels of intracellular Ki67, indicating a higher level of cellular activation associated with the HIV viremic state. We have further demonstrated that HIV-infected individuals have elevated levels of sfas and SFASL circulating in the serum during viremia when compared to the levels of these molecules during the aviremic state. These observations indicate a profound effect of HIV viremic state on the ability of NK cells to proliferate, undergo chemotaxis, and ultimately to survive in vivo. Future experiments will be focused on evaluating the turnover of NK cells in vivo after administration of BRDU. Such experiments will help us to understand the nature of NK cell proliferation and turnover in the HIV viremic state.
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