Heart disease in AIDS, particularly cardiomyopathy (CM), is an increasingly recognized clinical problem with as yet undefined pathogenetic mechanisms. Among the potential etiologies of AIDS CM are HIV-1 infection of cardiac myocytes and subsequent cardiac dysfunction, opportunistic infection, inflammatory reactions, cytokine effects, and cardiotoxicity of prescribed or illicit drugs. It seems probable that multiple factors may impact on the development of CM in AIDS. Transgenic mice (TG) are useful biological tools to explore mechanisms of cardiac function and disease. In AIDS models, TG offer novel ways to elucidate mechanisms of AIDS CM through combined in vivo and in vitro studies. With targeted and non-targeted TG, structural and functional effects of specific HIV-1 gene products on heart tissue may be addressed. The impact of environmental agents including therapeutics or cardiotoxins may also be defined. To address the complexity of AIDS CM using TG, an experimental approach has been employed in our laboratories to model the clinical condition. We utilize AIDS TG with generalized expression of HIV-1 gene products in CM models with combined antiretroviral regimens to define the cardiovascular effects of AIDS and its therapy on the structure and function of the murine heart. We are developing a series of cardiac specific TG bearing selected HIV-1 genes. These TG target the selected HIV-1 genes expressed in cardiac ventricular myocytes. Tissue-specific targeting of this type enables us to define structural and functional effects of specific HIV-1 gene products on the cardiac myocyte.