The overall aim of this project is to establish a transgenic mouse model to examine interactions between human immunodeficiency virus (HIV) and human cytomegalovirus (HCMV) which can contribute to the pathogenesis of Acquired Immune Deficiency Syndrome (AIDS). HCMV is one of the most common and importnat pathogens in patients with AIDS. HCMV possesses many similarities to HIV including suppression of the immune system and infection in vivo of monocyte/macrophages and endothelial cells. The ability of HYCMV to increase expression of HIV in vitro in the context of our recent colocalization of both viruses in single cells in brain tissue from AIDS patients with aberrant HCMV spread strongly suggests these viruses may potentiate each others growth. This application builds on these observations to develop a transgenic mouse model to examine specific interactions between HCMV and HIV in the animal. We have developed several founder lines of transgenic mice containing HCMV immediate-early (IE) genes which transactivate the HIV LTR. These HCMV IE mice will be crossed with several transgenic mouse lines containing different HIV constructs. Progeny from these crosses will be examined for tissue specific expression of HIV genes and HCMV IE genes by northern blot, in situ hybridization and immunocytochemistry. Phenotypic changes associated with expression of these viral genes will be determined by histopathology. We will determine whether HCMV IE mice can reactivate HIV expression in mice containing inactive HIV constructs. Finally, we will cross HCMV IE mice expressing viral transactivatying proteins in the brain with transgenic lines containing either HIV LTR gp160, gp120 or gp41 constructs to determine whehter we can target brain specific expression of HIV glycoproteins. These experiments will address the issue of whether HIV glycoproteins are directly involved in tissue damage in the CNS. Progeny mice will be examined for phenotypic changes associated with HIV glycoprotein expression in the brain. These transgenic mice will provide an important model to dissect disease processes of viruses restricted to human growth.
