The main objective of this research proposal is to understand the pathogenesis of oral complications associated with HIV infection, using a proteomic approach in a murine model of AIDS, the CD4C/HIV Tg mice. These Tg mice express some of the gene products of HIV-1 in cells normally targeted by HIV-1 infection in humans, namely CD4 CDS immature and CD4 CD8~ mature T cells and cells of the dendritic/macrophage lineage. These Tg mice develop an AIDS-like disease which is very similar to human AIDS, including immune defects and specific organ diseases (lung, heart and kidney). In particular, the oral mucosa of these Tg mice show enhanced susceptibility to oral candidiasis and allow chronic carriage of C. albicans, a pathology mimicking candidiasis described in individuals with AIDS. Because these pathological oral manifestations are associated with many other phenotypes very similar to those found in humans infected with HIV-1, we postulate that these Tg mice are relevant to human AIDS and that they constitute a very good model for the oral complications associated with HIV-1 in humans. In order to understand the pathogenesis of the oral mucosal changes favoring the development of candidiasis, we intend to use a proteomic approach on Tg oral mucosal tissues. In particular, we intend:
Aim 1 -To identify the major changes in protein profiles of saliva from CD4C/HIV Tg mice.
Aim 2 -To identify the major changes in protein profiles of total extracts of oral mucosal cells from CD4C/HIVTgmice.
Aim 3 -To generate sub-proteomic profiles of oral mucosal epithelial cells of CD4C/HIV Tg mice.
Aim 4 -To determine, using an inducible HIV transgene, whether changes in oral mucosal proteins induced by HIV expression are age-related.
Aim 5 -To identify the specific Nef-expressing cells of CD4C/HIV Tg mice associated with specific changes in protein profiles of oral mucosa. This research is especially relevant to public health in view of the high frequency of oral complications (especially candidiasis) in HIV-1 infected individuals.