HIV-1-infected intravenous drug abusers and homosexuals develop thrombocytopenia (HIV-1-ITP) which is particularly severe in drug abusers. Although originally thought to be immunologic peripheral platelet destruction, recent evidence suggests that the major mechanism may be due to impaired megakaryocytopoiesis and platelet production. We have recently demonstrated the presence of the HIV-1 CD4 receptor on human megakaryocytes (MK). Immature CD34+ MK express the highest levels of the CD4 antigen. We propose to determine whether: IA. Human bone marrow MK can be infected with HIV-1 via this CD4 receptor, and whether infection takes place during a narrow window of MK development in which all MK are CD4+; IB. MK development can be impaired due to the release of suppressor cytokines or lack of release of activation cytokines following infection of bone marrow accessory cells (T cells, monocytes, stromal cells) with HIV-1. We have recently noted a strong correlation between anti-idiotype antibody vs anti-HIV-1gp120 and thrombocytopenia (r=0.9, p<0.001); and the presence of high affinity anti-platelet IgG sequestered within immune complexes of HIV-I-ITP patients. We propose to determine whether: IIA. Such immune complexes and/or IIB. anti-platelet IgG can impair MK production and differentiation. An understanding of the role of HIV-1, CD4 and cytokines in the mechanism of thrombocytopenia in HIV-1-ITP patients could lead to therapeutic measures which could benefit patients with this bleeding disorder, as well as contribute fundamental insights into the regulation of an important hematopoietic cell.
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