CARDIOTOXICITY OF STREPTOCOCCAL PYROGENIC EXOTOXINS

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Cardiac complications including cardiomyopathy and endocarditis frequently complicate HIV infections particularly late in the course of the disease. Injection drug users infected with HIV are the most commonly affected. The etiology of HIV-related cardiotoxicity is unclear, although some believe it is related to concurrent infection with other bacterial and viral pathogens. This grantee is studying the cardiotoxicity of streptococcal pyrogenic enterotoxins and staphylococcal endotoxins on the heart. The long term goals of this project are two fold: 1) to evaluate the role of streptococcal pyrogenic exotoxins in causing both acute toxic shock line illnesses and delayed sequelae such as acute rheumatic fever and vascular diseases and 2) to analyze the structure function relationships among the streptococcal pyrogenic enterotoxins and staphylococcal enterotoxin. It is hoped that the latter studies will ultimately clarify the molecular mechanism of action of the toxins. R01HL42125 The objective of this program is to continue and expand ongoing studies on the mechanism by which pyrimidine nucleoside analog active against HIV such as 3'azido-3'-deoxythymidine and congeners exert toxicity on bone marrow and other cells. The elicitation of these mechanisms may permit the development of a combination therapy with modulating agents that protect or reverse host toxicity without impairment of the anti-HIV activity of the drug under scrutiny. This project has two major aims: 1) the description of the biochemical and molecular mechanism responsible for the effects of AZT and its metabolite, 3'-amino-3'-deoxythymidine (AMT) in human marrow cells; and 2) the detailed characterization of the enzymatic reduction of AZT to AMT in human hepatocytes with the evaluation of potential drug-drug interactions through the cytochrome P- 450 pathway.