The goal of this project is to understand the molecular mechanisms which regulate MHC class I gene expression in cells of the central nervous system. Over the past year, there have been three major efforts underway that are targeted on this objective. These are the identification of the mechanism of transcription factor control of beta 2-microglobulin and MHC class I gene expression in (1) mouse brain; (2) mouse embryonal carcinoma cells treated with retinoic acid; and (3) human fetal glial cells infected with HIV-1. The principle findings are: (1) the absence of MHC class I and beta2-microglobulin gene expression in the brain is due, at least in part, to the absence of transcription factor binding to promoter elements of these genes; (2) retinoic acid treatment of embryonal carcinoma cells induces heterodimers of NFkappaB p50/p65 to bind to MHC class I enhancers, resulting in increased MHC class I gene expression; and (3) reactivation of HIV~1 gene expression induced by TNF~alpha and IL~1 beta in human fetal glial cells involves the binding of NFkappaB p50/p65 to the HIV-1 LTR.
