Abstract
Long terminal repeat (LTR) of human immunodeficiency virus (HIV) type 1 is activated by thyroid hormone (T3) receptor alpha (T3R alpha) in the absence of ligand. Addition of T3 reverses this effect. This activity is mediated by a high affinity T3 response element (T3RE) within the HIV-1 LTR, termed the HIV-T3RE (bases -74 to -50), which coincides with the Sp1 element as demonstrated by mobility shift, DNaseI footprinting, and methylation interference analyses. HIV-T3RE mediates ligand-independent activation of transcription by T3R alpha when linked to a heterologous promoter. In addition, the viral transactivator Tat synergizes with T3R alpha to activate the HIV-1 LTR in the absence of T3, which is relieved in its presence. These findings have implications for the possible control of HIV-1 LTR activity by T3.
Highlights
human immunodeficiency virus (HIV)-11 gene expression is regulated by binding and interplay of both viral and cellular host proteins to the HIV-1 Long terminal repeat (LTR)
Ligand-independent Activation of HIV-1 LTR by T3 are mediated by nuclear receptors (T3Rs)␣—To determine the effect of T3R and T3 on the activity of the HIV-1 LTR, a reporter construct in which the HIV-1 LTR drives expression of the chloramphenicol acetyl transferase (CAT) gene (HIV-1-CAT) [16] was cotransfected into CV-1 cells (African green monkey kidney cells) with expression vectors for T3R␣
Half-maximal inhibition of T3R␣-mediated activation of HIV-1-CAT expression by T3 occurred at 4 ϫ 10Ϫ9 M T3, and maximal inhibition was achieved at 10Ϫ7 M (Fig. 1B)
Summary
HIV-11 gene expression is regulated by binding and interplay of both viral and cellular host proteins to the HIV-1 LTR (see Refs. 1 and 2). Tients with AIDS and ARC, with the most frequent alterations being low serum T3 levels and free T3 indexes and high thyronine-binding globulin levels T3Rs are encoded by the c-ErbA␣ and c-ErbA genes [7, 8] These proteins belong to the superfamily of nuclear receptors, which are ligand-activated transcription factors related in their highly conserved DNA binding domain and relatively well conserved ligand binding domain [9, 10]. In light of consistent alterations in T3 levels in patients with AIDS and ARC [4, 5], we determined whether T3Rs and T3 affect HIV-1 LTR activity. These findings suggest that T3 and T3R␣ may have a role in the regulation of HIV-1 LTR activity
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