TISSUE FACTOR AS A SURROGATE MARKER OF HIV

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Monocytes-macrophages are important regulatory cell of the immune system. During an infection, macrophages show altered regulation; however, presently no good system exists for evaluation of macrophage function that can be monitored during the course of HIV-related disease progression. To examine mechanisms for evaluation of macrophage function during an infection, I have evaluated the regulation of cytokine production by macrophages obtained from individuals infected with HIV. During these studies, I have found that steady state levels of lymphokine stimulated tissue factor (TF) mRNA are decreased in individuals with symptomatic HIV infection and that there is a continuum of diminished TF function in patients with asymptomatic disease, ARC, and AIDS. In contrast, monocytes from AIDS and ARC patients continue to show notable responses of tumor necrosis factor and interleukin 1-beta. Based on these observations we hypothesize that TF may be an excellent surrogate marker for monitoring the progression of the disease and may be useful as an indicator of improved immunologic function in individuals receiving beneficial therapy. In this proposal, I intend to monitor induced levels of TF in patients receiving treatment in specific ACTG protocols under study at the UCSD ACTU. Patients in these studies will be monitored at fixed intervals over the one year period of this proposal. Monocytes collected will be stimulated with LPS for 4 hrs, RNA extracted, and an aliquot of cells frozen TF RNA and protein levels form each individual will be assayed simultaneously. Additionally, since in vitro signals are provided to monocytes by T-cells, monocytes will be stimulated by monocyte procoagulant inducing factor (MPIF) to determine if MPIF induced TF is a more sensitive marker of monocyte function than LPS-induced TF. Thus, the utility of both LPS-MPIF- induced TF will be evaluated as surrogate markers for monocyte function and compared with the clinical outcomes in patients involved in ACTG treatment protocols.