The Laboratory of Oral Medicine has developed several transgenic mouse lines. The one that has been studied the most was made from a subgenomic, noninfectious HIV-1 proviral construct, driven by the HIV LTR, that lacks gag and pol, but includes env and the accessary genes tat, rev, nef, vif, vpr and vpu. The expression of HIV in infected cells is controlled in part by host cellular factors which recognize cis-acting regulatory elements of the promoter as well as post transcriptional regulatory signals present in the viral mRNA. The objective of this project is to use transgenic mice to study the pathology induced by different HIV genes and to define relevant transcriptional and post-transcriptional factors. The long-term goal is to identify new targets and factors for a molecular based therapy to inhibit viral replication. HIV transgenic heterozygous mice with a gag-pol deletion in the proviral genome, showed lesions in a number of different organs, particularly prominent in the kidney and skin. The kidney pathology is characterized by glomerulosclerosis, proteinuria, and progressive renal failure. The picture is very similar to that found in humans with HIV-associated nephropathy (HIVAN). The skin pathology is characterized by epidermal hyperplasia and focal epidermal papillomas which becomes more prominent with age. Perhaps the most exciting finding is with the transgenic homozygous mice. These animals are normal in appearance and weight at birth. However, within a few days, the homozygous mice, in contrast to the heterozygous mice, show a scaly hyperkeratosis over the entire body surface, develop a wasting syndrome and die within several weeks. These findings suggested that a maternal factor might be protecting the homozygous mice up to the time of birth. We very recently found that human chorionic gonadotropin (hCG) can prevent the development of both the skin lesions and the wasting syndrome and prevent death. In addition, HIV transcripts and protein are markedly decreased in the skin and muscles following treatment with hCG. In contrast, other pregnancy related hormones, such as estrogen and progesterone, increase HIV transcripts and protein and accelerate the time to death. Studies on the mechanism of hormonal modulation of HIV gene expression are now underway. Other hormones and factors which activate and suppress HIV transcripts have been identified and are being investigated in greater depth. Factors which prevent wasting, decrease HIV transcripts and extend life in the HIV transgenic mouse model will be considered for clinical trials.
