Immunopathic platelet destruction leading to thrombocytopenia occurs in a significant number of patients infected with human immunodeficiency virus type 1 (HIV). The mechanism of antibody platelet interaction leading to increased platelet removal remains obscure despite much investigation over the past six years. One consistent finding that has emerged from these studies is the presence of increased amounts of immunoglobulins associated with platelets from most HIV infected patients, including many with normal platelet counts and no history of thrombocytopenia. This project has been designed to accomplish two major goals: 1) to elucidate the mechanism of HIV-associated immunopathic platelet destruction (HIV-ITP), and 2) to determine the relevance of elevated platelet immunoglobulin levels in the HIV infected state.
The specific aims of this proposal will test the hypothesis that the mechanism of HIV-ITP is not due to the increased platelet load of immunoglobulins (or immune complexes), but is most likely due to autoantibody. In addition, the specific aims will test the second hypothesis, that increased platelet immunoglobulin levels are secondary to a direct HIV effect on megakaryocytes or platelets and do not reflect equilibration with circulating immunoglobulins or immune complexes. As part of the proposed study, two cohorts of HIV seropositive patients, one with evidence of ITP and the other with normal platelet counts will be recruited and followed at regular intervals. A series of in vitro platelet and serologic studies will be performed in conjunction with platelet survival studies to determine how platelets relate to the humoral immune system in the HIV infected state and when that relationship leads to platelet destruction. Rhesus monkeys infected with simian immunodeficiency virus display clinical similarity to HIV infected humans, including a similar incidence of thrombocytopenia. Proposed work on SIV infected monkeys includes platelet survival studies on thrombocytopenic animals and in vitro platelet studies on both non- thrombocytopenic and thrombocytopenic animals. This work will be a major step in the development of a simian model for retroviral induced platelet abnormalities.
