DIVERGENT TRANSCRIPTIONAL REGULATION AMONG EXPANDING HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 SUBTYPES

The current AIDS pandemic represents the uneven spread of multiple gen etically related subtypes (A to J) of human immunodeficiency virus typ e 1 (HIV-1). Notably, HIV-1 E in southeast Asia and HIV-1 C in sub-Sah aran Africa are expanding faster and are likely of greater global sign ificance than the HIV-1 B subtype prevalent in the United States and E urope. While many studies have focused on genetic variation among stru ctural genes, we chose to conduct a comparative analysis of the long t erminal repeats of HIV-1 E and HIV-1 C isolates and report subtype-spe cific differences in enhancer copy numbers and sequences, as well as d ivergent activation in response to the cellular transcriptional activa tors Rel-p65 and NFATc and viral Tat. This study is the first to ident ify functional distinctions in promoter architecture between HIV-1 sub types and raises the possibility that regulatory divergence among the subtypes of HIV-1 has occurred. Divergent transcriptional regulation m ay explain some of the epidemiologically observed differences in trans mission and pathogenesis and underscores the need for further comparat ive analysis of HIV-1 regulation.