The effect of trans-acting factors on cis-acting DNA elements on the HIV-1 promoter are the principal determinant regulating transcriptional activation and repression. Host factors that limit viral replication can contribute to the emergence and maintenance of proviral reservoirs. The current paradigm is that this sub-population of latently infected cells confers a biological advantage to the virus by facilitating evasion of immunologic responses and therapeutic strategies resulting in life-long and persistent infection. In this report, we show that ectopic expression of the nuclear phosphoprotein, c-Myc can inhibit HIV-1 gene expression and virus production in CD4+ T-lymphocytes. The effect exerted does not appear to involve other known functions of c-Myc such as proliferation, or apoptosis. The mechanism does implicate c-Myc in a direct role. We have found evidence that c-Myc can specifically recognize the HIV-1 initiator element surrounding the start site of transcription and linker scanning mutagenesis experiments confirmed a loss of c-Myc-mediated repression in the absence of this region. Moreover, we show that c-Myc can interact with the initiator binding proteins YY-1 and LBP-1 and can cooperate with these factors to synergistically repress HIV-1 LTR transcription. Taken together, these results indicate that c-Myc is an important regulator of HIV-1 transcription that potentially contributes to the latent proviral state.
Copyright 2004 Wiley-Liss, Inc.