Secondary (2 degrees) bacterial, fungal and viral infections continue to occur in a significant fraction of HIV-1 infected patients despite the improvements in treatment that have come from contemporary anti-retroviral drugs. We postulate that 2 infections occur mainly in patients who have acquired significant defects in their innate immune responses, especially the monocyte-dependent responses that are critical for host defense against intracellular infections. Indeed we found that monocytes from CDC stage B/C as opposed to CDC stage A patients are often weakly phagocytic for bacteria; their ability to migrate across confluent endothelial barriers is diminished and they often produce reactive oxygen intermediates inappropriately. These functional abnormalities reflect a disordered display of the beta-integrins needed for appropriate cell-cell interactions, and are associated with the presence of circulating fibronectin (FN) fragments and soluble immune complexes. We can recreate many of the monocyte functional abnormalities seen in vivo by exposing these cells to soluble immune complexes or cell binding FN fragments in vitro. We now propose to study a carefully characterized cohort of 369 patients. In the past 2 years, 84 of these patients were hospitalized on one or more occasions for treatment of 2 degrees infections. Occurrence of 2 degrees infection was inversely related to adherence to prescribed anti- retroviral therapy and to the magnitude of the response to these drugs as measured by changes in viral load and CD4 T cell count. To determine whether defects in monocyte function predispose to 2 degrees infection and to investigate whether immune complexes and fibronectin degradation fragments are responsible for the monocyte functional defects we see, we propose to study these patients and compare them to patients with similar viral loads and CD4 T cell counts who have not been hospitalized for 2 degrees infection in this interval. An important part of the proposed studies is an intensive intervention designed to increase adherence to anti-retroviral drug therapy. We postulate that patients predisposed to infection will have circulating cell binding fibronectin fragments. These bind to monocyte CD29/CD49e and stimulate cell surface display of proteinase-3, which, in turn, degrades CD49e and other molecules, used by monocytes in defense against microbial pathogens. We further postulate that treatments that improve adherence to anti-retroviral drug therapy will reduce the circulating levels of immune complexes, fibronectin degradation products and other agents that degrade monocyte function, thereby reducing the occurrence of 2 degrees infections.
