Abstract
Acquired immunodeficiency syndrome (AIDS) is a result of replication of the human immunodeficiency virus type 1 (HIV-1) predominantly in CD4+ T lymphocytes and macrophages. However, most of these cells in vivo are immunologically quiescent, a condition restricting HIV-1 replication. Vpr is an HIV-1 virion protein suspected to enhance HIV-1 replication in vivo. We demonstrate in this report that Vpr specifically activates HIV-1 long terminal repeat (LTR)-directed transcription. This effect is most pronounced on a minimal promoter from HIV-1 LTR containing the TATA box and binding motifs for the ubiquitous cellular transcription factor Sp1. Evidence is presented that Vpr interacts with Sp1 when Sp1 is bound to the Sp1 motifs within the HIV-1 LTR Both Vpr-Sp1 interaction and Vpr trans-activation require a central Leu/Ile-rich domain in Vpr. Our findings suggest that Vpr trans-activation through Sp1 is most critical for the immediate early transcription of HIV-1 when other positive regulators, such as NF-kappa B, are limited or inactive, a condition presumably present in vivo. By interacting with Sp1, Vpr also has the potential to influence cellular gene expression and cellular functions. Thus, therapeutic approaches directed toward blocking the Vpr trans-activation function could prove valuable in treating AIDS.
Highlights
HIV-11 is the etiological agent of Acquired immunodeficiency syndrome (AIDS)
To understand the role of human immunodeficiency virus type 1 (HIV-1) accessory regulatory genes during HIV-1 replication and pathogenesis, we focused on the vpr gene product, which is a 96-aa protein produced late in the virus life cycle and assembled into the virion through binding to Gag [11,12,13]
We identified the ubiquitous cellular transcription factor Sp1 to be a target for HIV-1 Vpr
Summary
HIV-11 is the etiological agent of AIDS. The hallmark of AIDS is the slow but progressive depletion of CD4ϩ-T cells, a class of T cells crucial for immune functions. The HIV-1 Vpr protein in peripheral blood of HIV-1-infected people was shown to activate HIV-1 replication in latently infected cells [3, 4] Great efforts have been made toward understanding the function of the so-called accessory regulatory genes, namely vif, vpr, vpu, and nef These genes are generally non-essential for HIV-1 to replicate in activated T cells. These results are consistent with the notion that Vpr may play a role during the nuclear migration of the pre-integration complex [18] They were consistent with the hypothesis that Vpr can function in the nucleus to trans-activate HIV-1 [19]. Our results are consistent with the notion that Vpr function is most critical for the immediate early transcription of HIV-1 when other positive regulators, such as NF-B, are limited or inactive, a condition presumably present in vivo
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