Autoimmune mechanisms are known to play a role in the thrombocytopenia observed in individuals infected with the human immunodeficiency virus (HIV) who suffer from the Acquired Immune Deficiency Syndrome (AIDS). However, immunologic mechanisms alone are unlikely to account for all aspects of the pathogenesis of thrombocytopenia seen in AIDS. Among these other mechanisms are possible direct effects of the HIV, or its associated proteins, on the development of megakaryopoietic progenitors in the bone marrow, or the ability of these cells to carry out thrombopoiesis, the process of platelet production. It is also possible that these effects may be brought about indirectly by effects of the virus, or viral proteins, on marrow stromal and accessory cells supportive of megakaryocytopoiesis. To investigate these issues, The applicants propose the following four specific aims: I. Determine the effect of HIV infection on megakaryopoiesis and platelet formation. They will infect human megakaryocytic cells at various stages of development with HIV-1 and HIV-2 viruses and examine the ability of these cells to differentiate into mature megakaryocytes and form platelets. If these processes are impaired, they will determine the mechanism(s) involved. II. Characterize the chemokine receptors on megakaryocytes and the influence of their corresponding ligands on megakaryopoiesis. They will characterize the chemokine receptors displayed on uninfected and infected megakaryocytes, and study the influence of these receptor-ligand pairs on the developmental biology of these cells. These studies will shed light on the function of these chemokines during megakaryocytopoiesis and thrombopoiesis. III. Investigate the role of HIV proteins and HIV-induced cytokines on thrombocytopenia. They will evaluate the influence of viral proteins and inflammatory cytokines elaborated during infection by accessory cells on the developmental biology of megakaryopoietic precursors and mature cells. IV. Develop strategies for preventing HIV-induced thrombocytopenia. Inhibitory mutants of chemokines have already been developed and shown to prevent HIV infection. Based on findings in the first 3 specific aims, they plan to test blocking chemokines and monoclonal antibodies, and blocking of various cytokines on megakaryopoiesis both ex vivo and in NOD/SCID (non obese diabetic/severe combined immunodeficiency) mice/human hematopoietic chimeras. In toto, the studies proposed in this grant will increase the knowledge about pathogenesis of AIDS associated thrombocytopenia and may lead to development of new strategies for its treatment of prevention.
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