HIV infection alters a variety of cellular functions, including cell adhesion, localization, and secretion of proteases and cytokines. The goals of this project are to determine the functions of integrins and secreted molecules in the response of human monocytes to HIV infection, the mechanisms by which HIV regulates these molecules, their roles in AIDS pathogenesis, and approaches to inhibiting these alterations. Infection of human monocytes by HIV-1 resulted in marked alterations in cell-cell adhesion resulting from changes in levels and functions of beta2 integrins and proteases. Specifically, infected monocytes displayed enhanced adhesion to other monocytes and to microvascular endothelial monolayers. Infected monocytes also induced the matrix metalloproteinase MMP-9. Endothelial cell monolayers to which these monocytes attached were disrupted in a process that could be inhibited by protease inhibitors. We are elucidating roles of the HIV regulatory molecule Tat in these events. Tat treatment mimicked many of the effects of HIV-1 infection. It induced cytokine synthesis and substantial secretion of the cytokines TNF-alpha, IL-1 alpha, IL-6, and IL-8. Tat also induced cell-cell aggregation of treated (but uninfected) monocytes, which was attributable to altered synthesis, surface expression, and function of alpha-2 integrins. Moreover, HIV-Tat treatment alone induced MMP-9 synthesis. Antibodies against TNF-alpha and IL-1 alpha induced by Tat substantially reduced the effects of Tat on MMP-9 production, adhesion, and endothelial damage. These studies suggest roles for extracellular Tat and monocyte cytokines, integrins, and proteases in the pathogenesis of AIDS. HIV-Tat induces monocyte activation with selective, enhanced cytokine production, which results in enhanced ability of monocytes to adhere to and disrupt endothelium, and then to invade by means of enhanced integrin and protease expression. We propose that such HIV-activated cells have increased propensity to invade tissues; such tissue macrophages are known to be major reservoirs of HIV virus. These findings suggest that approaches using specific inhibitors of soluble Tat function, or of certain cytokines, or of other steps in monocyte activation and invasion might provide new insights into AIDS pathogenesis and novel approaches to prevention.
