EVIDENCE THAT A CELL-CYCLE REGULATOR, E2F(1), DOWN-REGULATES TRANSCRIPTIONAL ACTIVITY OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROMOTER

Proliferation of eukaryotic cells is orchestrated by a series of cellu lar proteins which participate in various stages of the cell cycle to guide the cell through mitosis. Some of these proteins, including E2F( 1), play a critical role in G(1) and S phases by coordinately regulati ng expression of several important cell cycle-associated genes. On the basis of recent observations indicating a block in human immunodefici ency virus type 1 (HIV-1) replication in cells arrested in G(1)/S phas e of the cell cycle, we sought to evaluate the regulatory action of E2 F(1) on transcription from the HIV-1 long terminal repeat (LTR). Resul ts from transient transfection of cells with an E2F(1) expression plas mid indicated that E2F(1) has the ability to suppress basal transcript ional activity of the LTR and to diminish the extent of the Tat-induce d activation of the viral promoter, Deletion analysis of the HIV-1 LTR in transfection studies revealed the presence of two major elements r esponsive to E2P(1) repression located distally (-454 to -381) and pro ximally (-117 to -80) with respect to the +1 transcription start site. E2F(1)-mediated suppression of LTR activity was observed in a wide ra nge of human cell lines, Expression of E2F(1) by a transgene showed an inhibitory effect on the levels of reverse transcriptase activity obt ained upon introduction of the proviral genome into cells. The data pr esented in this study suggest that cellular regulatory proteins involv ed in the progression of cells through the mitotic cycle could play cr ucial roles in determining the efficiency of HIV-1 replication during the various stages of infection. The possible roles of these factors i n viral latency and activation are discussed.