Possible Tissue Glucocorticoid Hypersensitivity in Human Immunodeficiency Virus type-1 (HIV-1) Infection

T. Kino

Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20 852, U.S.A.

Acquired immunodeficiency syndrome (AIDS), caused by human immunodeficiency virus type 1 (HIV-1) infection, develops profound deterioration of the host immune system. AIDS patients also present with variety of manifestations including myopathy/muscle wasting, osteoporosis, dementia and growth retardation in children as well as dyslipidemia and insulin resistance/overt diabetes mellitus, accompanied by a characteristic lipodystrophy phenotype [1] [2]. In addition to the suppression of host immune function, many of these changes can be induced by exogenously administered glucocorticoids and are seen in hypercortisolemic patients with endogenous Cushing syndrome. It is, therefore, possible that some unknown factor(s) might up-regulate glucocorticoid actions in certain tissues of AIDS patients.

Based on the above clinical evidence, we explored the possibility of glucocorticoid hypersensitivity in AIDS/HIV-1 infection, focusing on one of the HIV-1 accessory proteins, Vpr. This viral molecule is a 96-amino acid virion-associated protein and has multiple functions. Vpr is known to enhance the replication of HIV-1 virus in lymphocyte- and monocyte-derived cell lines. It also behaves as a transcriptional activator of several viral promoters and as an enhancer of HIV-1 long terminal repeat (LTR) promoter activated by Tat. Vpr also causes host cell arrest in the G2/M phase of the cell cycle, and induces terminal differentiation in some cell lines. Furthermore, Vpr increases the translocation of the HIV-1 pre-integration complex into the nucleus, and promotes efficient infection of non-dividing macrophages. Since Vpr circulates at detectable levels in HIV-1-infected individuals and is able to penetrate the cell membrane, its effects may be extended to cells not infected by HIV-1.

We found that this small HIV-1 protein enhances transcriptional activity of the glucocorticoid receptor (GR) on its responsive promoters by functioning as a coactivator of steroid hormone receptors [3]. Indeed, Vpr contains a nuclear receptor signature motif LXXLL at amino acids 64 to 68, which is used by host nuclear receptor coactivators to bind the receptors. Vpr mimics host p160 nuclear receptor coactivators, functioning as an adaptor molecule between promoter-bound GR and p300/CBP coactivators in a glucocorticoid-responsive promoter by binding to amino acids 2045 to 2191 of p300, which also physically interact with host p160 coactivators [4]. To address Vpr effect on endogenous glucocorticoid-responsive molecules, we created the Vpr peptide in a baculovirus system and tested it on the glucocorticoid-responsive cytokine production by human peripheral monocytes/macrophages. We found that extracellularly administered Vpr enhanced the suppressive actions of the ligand-activated glucocorticoid receptor on Interleukin (IL)-12 secretion and its mRNA expression by these cells, a well-known cytokine that plays a critical role in the development of the T-helper 1 lymphocytes and are regulated by glucocorticoids [5]. The GR antagonist RU486 inhibited this effect. Moreover, Vpr changed the expression of an additional 5 glucocorticoid-responsive genes in the same direction as dexamethasone.

In a separate experiments, we also found that Tat, another key HIV-1 accessory protein, moderately potentiates GR activity [6]. Indeed, the coactivator complexes of the HIV-1 LTR and the glucocorticoid-responsive promoters both include p160 coactivators and use similar coactivator and elongation complexes for their transcription (Fig. [1]). Tat may function as an adaptor molecule efficiently stimulating the processes of transcription initiation and elongation, through potentiation of the coupling of p160 coactivators and the positive-acting transcription elongation factor b (p-TEFb) complex.

Fig. 1 Schematic models of HIV-1-LTR and glucocorticoid-responsive mouse mammary tumor virus (MMTV)-LTR transactivation modulation by coactivators and p-TEFb. These models do not show the dynamic, sequential interactions between the reactants, which would be essential to explain the presence of multiple, overlapping binding sites that these proteins have for each other.

Therefore, through its encoding proteins, Vpr and Tat, HIV-1 may facilitate the transcription of genes encoding its own proteins by directly stimulating viral proliferation. On the other hand, by inducing hypersensitivity to glucocorticoids, these proteins contribute to the proliferation of the virus indirectly by suppressing the host immune system (Fig. [2]). Extensive further clinical and basic investigations are crucial to examine the clinical importance of glucocorticoid hypersensitivity and to develop novel effective therapeutic approaches in AIDS.

Fig. 2 Possible effects of HIV-1 Vpr and Tat on the viral replication/proliferation, immune suppression and clinical manifestations seen in AIDS patients.

References

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