TRANSGENIC MODEL FOR HIV/OPPORTUNISTIC INTERACTIONS

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.