DIFFERENTIAL REGULATION OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-2 ENHANCER IN MONOCYTES AT VARIOUS STAGES OF DIFFERENTIATION

We have demonstrated that stimulation of the human immunodeficiency vi rus type 2 (HIV-2) enhancer in T cells is dependent upon at least four cis-acting elements, including two purine-rich binding sites, PuB1 an d PuB2, which are capable of binding members of the ets family of prot o-oncogenes, the pets (peri-ets) site, which lies just upstream of the PuB2 site, and a single KB site (D. M. Markovitz, M. Smith, J. M. Hil finger, M. C. Hannibal, B. Petryniak, and G. J. Nabel, J. Virol. 66:54 79-5484, 1992). In this study, we examined the regulation of the HIV-2 enhancer in cells of monocytic lineage. We found that in immature mon ocytic cell lines, the HIV-2 enhancer is markedly induced by phorbol e sters and that all four cis-acting elements are required for activatio n. In mature monocytic cells, constitutive activity is high, with only modest stimulation following phorbol ester treatment. Mutation of any of the four cis-acting elements resulted in greatly reduced basal exp ression in mature monocytes. This is in contrast to HIV-1, in which de velopmentally controlled expression of the enhancer in monocytes is me diated largely through the kappaB sites alone [G. E. Griffin, K. Leung , T. M. Folks, S. Kunkel, and G. J. Nabel, Nature (London) 339:70-73, 1989]. Further, we demonstrated that although both Elf-1, an ets famil y member with significant similarity to the drosophila developmental r egulatory protein E74, and Pu.1, a monocyte- and B-cell-specific membe r of the ets family, bind the purine-rich enhancer region, Elf-1 is th e protein which binds predominantly in vivo. A nuclear factor(s) which binds the pets site, an element which has been described only in HIV- 2, was detected in extracts of all of the monocytic cells tested. Thes e findings indicate that the mechanism by which cellular factors regul ate HIV-2 enhancer function in monocytic cells differs significantly f rom that of HIV-1 and may offer a partial explanation for the differen ces in the biological and clinical characteristics of the two viruses.