THE PERI-KAPPA-B SITE MEDIATES HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-2 ENHANCER ACTIVATION IN MONOCYTES BUT NOT IN T-CELLS

Human immunodeficiency virus type 2 (HIV-2), like HIV-1, causes AIDS a nd is associated with AIDS cases primarily in West Africa HIV-1 and HI V-2 display significant differences in nucleic acid sequence and in th e natural history of clinical disease. Consistent with these differenc es, me have previously demonstrated that the enhancer/promoter region of HIV-2 functions quite differently from that of HIV-1. Whereas activ ation of the HIV-1 enhancer following T-cell stimulation is mediated l argely through binding of the transcription factor NF-kappa B to two a djacent kappa B sites in the HIV-1 long terminal repeat, activation of the HIV-2 enhancer in monocytes and T cells is dependent on four cis- acting elements: a single kappa B site, two purine-rich binding sites, PuB1 and PuB2, and a pets site. We have now identified a novel cis-ac ting element within the H1V-2 enhancer, immediately upstream of the ka ppa B site, designated peri-kappa B. This site is conserved among isol ates of HIV-2 and the closely related simian immunodeficiency virus, a nd transfection assays show this site to mediate HIV-2 enhancer activa tion following stimulation of monocytic but not T-cell lines. This is the first description of an HIV-2 enhancer element which displays such monocyte specificity, and no comparable enhancer element has been cle arly defined for HIV-1. While a nuclear factor(s) from both peripheral blood monocytes and T cells binds the peri-kappa B site, electrophore tic mobility shift assays suggest that either a different protein bind s to this site in monocytes versus T cells or that the protein recogni zing this enhancer element undergoes differential modification in mono cytes and T cells, thus supporting the transfection data. Further, whi le specific constitutive binding to the peri-kappa B site is seen in m onocytes, stimulation with phorbol esters induces additional, specific binding. Understanding the monocyte-specific function of the peri-kap pa B factor may ultimately provide insight into the different roles mo nocytes and T cells play in HIV pathogenesis.