Activation of the human immunodeficiency virus type I long terminal repeat by 1α,25-dihydroxyvitamin D3

Abstract

The genetic predisposition of the host and the virus is the most important determinant for prediction of the course of human immunodeficiency virus type I (HIV-1) viral infection and acquired immune deficiency syndrome (AIDS) progression. Transcription from the HIV-1 long terminal repeat (LTR) is a crucial step for viral replication. Here, we describe a stimulatory role of the vitamin D receptor (VDR) on HIV-1 LTR transactivation. Transient transfections reveal that VDR activates the LTR in HeLa, U937, and Cos-1 cells in a ligand-dependent manner. 1a,25-Dihydroxyvitamin D3 (vitD3) promotes activation of a minimal LTR construct (from nucleotides K35 to C89), lacking a previously described hormone response element that binds several nuclear receptors. NF-kB (nuclear factor-kappa B) and Sp1-binding sites, which are responsible for most basal LTR activity in HeLa cells, are also dispensable for vitD3-dependent HIV-1 transcription. Although the tat response element element is not required for VDR-mediated HIV-1 gene expression, the viral protein Tat acts in a synergistic manner with the receptor to stimulate LTR activity. Furthermore, our data also show cooperation of the receptor with various cellular coactivators for HIV-1 transactivation by vitD3. Paradoxically, mutations in the VDR ligand-dependent transcriptional activation function-2 that abrogate vitD3-dependent stimulation through classical vitamin D response elements, do not reduce vitD3-mediated LTR transactivation. Furthermore, point mutations in the DNA-binding domain that abolish receptor binding to consensus DNA sequences do not affect ligand-dependent HIV-1 stimulation. These results show that VDR activates the HIV-1 LTR through different mechanisms, including nonclassical nuclear receptor transcriptional actions that may ensure viral transcription under different physiological scenarios.

Reciprocal seasonal variation in vitamin D status and tuberculosis notifications in Cape Town, South Africa

“…Vitamin D deficiency is associated with susceptibility to active TB in both the absence and the presence of HIV infection, but the association is stronger (24), suggesting a potential direct causal relationship between vitamin D deficiency and susceptibility to active TB. In HIV-infected people, vitamin D might also indirectly enhance antimycobacterial immunity by slowing progression of HIV disease (25,26), although studies investigating the effect of vitamin D metabolites on HIV replication in vitro report conflicting results (27)(28)(29)(30)(31). It is biologically plausible, therefore, that vitamin D deficiency impairs antimycobacterial responses in HIV-infected adults and that this phenomenon explains the association between vitamin D deficiency and susceptibility to active TB that we report here.…”

Antimicrobial implications of vitamin D

“…Nevado et al used U937 cells as a model for mononuclear cells (a target for HIV) and demonstrated that VDR and its ligand 1,25-D 3 have a role in transactivation of the long terminal repeat sequence of HIV type 1, which is a crucial element in viral replication. 66 The exact nature of this influence has yet to be fully elucidated. HIV entry into monocytes depends on chemokine receptor CCR5, 67 and vitamin D has a dual role in potentially blocking this step in the infectious pathway.…”

Vitamin D and Innate Immunity

“…Another study found no association between a specific polymorphism and protection against HIV infection in a population of injection drug users, but did find a correlation between specific VDR haplotypes (blocks of polymorphisms) [60]. The authors concluded that protective VDR polymorphisms were associated with reduced VDR function, consistent with vitamin D signaling promoting HIV infection, and noted in an in vitro study that the 1,25D-bound VDR could activate the HIV1 long terminal repeat [61]. Given the recent studies linking vitamin D sufficiency to reduced HIV progression and mother-to-child transmission [50,51] further work regarding links between VDR polymorphisms and HIV appears warranted.…”