Modulation of HIV-1 virulence via the host glucocorticoid receptor: towards further understanding the molecular mechanisms of HIV-1 pathogenesis

Abstract

The glucocorticoid receptor (GR) is a steroid receptor that regulates diverse functions, which include the immune response. In humans, the GR acts via binding to cortisol, resulting in the transcriptional modulation of key host genes. Several lines of evidence suggest that the host GR could be a key protein exploited by HIV at multiple levels to ensure its pathogenic success. Endogenous and therapeutic glucocorticoids play important roles in patients with HIV due to their well-established effects on immune function. AIDS patients develop glucocorticoid hypersensitivity, consistent with a mechanism involving an HIV-1-induced increase in expression or activity of the GR. Both the HIV-1 accessory protein Vpr and the host GR affect transcription of viral proteins from the long terminal repeat (LTR) region of the HIV-1 promoter. In addition, Vpr modulates host GR function to affect transcription of host genes, most likely via direct interaction with the GR. Vpr appears to regulate GR function by acting as a co-activator for the GR. Since both the GR and Vpr are involved in apoptosis in T cells and dendritic cells, crosstalk between these proteins may also regulate apoptosis in these and other cells. Given that cortisol is not the only ligand that activates the GR, other endogenous as well as synthetic GR ligands such as progestins may also modulate HIV pathogenesis, in particular in the cervicovaginal environment. Investigating the molecular determinants, ligand-selectivity and role in HIV pathogenesis of the GR-Vpr interaction may lead to new strategies for development of anti-HIV drugs.

The Glucocorticoid Receptor in Retroviral Infection

“…Vpr also potentiated the glucocorticoid-induced inhibition of other immunologically important cytokines such as IL-2, IL-10, TNF alpha and IL-4, all of which are NFκB -dependent (Fakruddin & Laurence, 2005). Both the GR and Vpr are involved in the apoptosis in T cells and dendritic cells (Hapgood & Tomasicchio, 2010;Bruland et al, 2003b). In addition, patients with AIDS and normal cortisol secretion have manifestations compatible with glucocorticoid hypersensitivity of the immune system, such as suppression of innate and cellular immunity.…”

“…The ability of activated GR to block NFkB's transactivation of these genes is likely important in mediating the immunosuppressive effect of glucocorticoids (Ito et al, 2001). GRE are present in the genomes of most gamma-retroviruses (Bruland et al, 2003a, Rodriguez & Goff, 2010, Pages et al, 1995 and HIV-1 based lentiviruses (Ghosh, 1992;Mitra et al, 1995;Hapgood & Tomasicchio, 2010). NFkB response elements are generally absent in gamma-retroviruses, but present in HIV-1, making GR-mediated regulation of lentiviral vectors derived from the HIV-1 backbone more complex.…”

“…These influences can be both positive and negative. (Hapgood & Tomasicchio, 2010;Kino et al, 1999;Ayyavoo et al, 1997a;Mirani et al, 2002) The overall effect of glucocorticoids on lentiviral promoter activity, therefore, can be difficult to predict. This may explain the confusing, and often contradictory, results on the effect of glucocorticoids on HIV-1 progression obtained by different research groups (Kino et al, 2000).…”

“…Most, if not all, of these effects are mediated through their interactions with the GR (Herold et al, 2006). Activated GR can interfere with the signaling pathways of AP-1 and NFκB, two key host transcription factors that regulate expression of pro-inflammatory genes and other genes involved in immune responses (Hapgood & Tomasicchio, 2010;De Bosscher et al, 2003;Smoak & Cidlowski, 2004) Vpr enhances the immunosuppressive effect of endogenous and therapeutic glucocorticoids (Mirani et al, 2002;Kino et al, 1999). Vpr administered extracellularly potentiated the glucocorticoid-induced suppression of mRNA expression and secretion of IL-12 by dendritic cells (Kim et al, 2001).…”

“…To combat this limitation, the excised GRE can be restored within the second internal promoter. Even without restoring GREs in SIN vectors, however, activated GR continue to have an effect on lentiviral behavior due to the presence of GRE and NFkB responsive sequences in regions other than U3 (Soudeyns et al, 1993;Hapgood & Tomasicchio, 2010;Mitra et al, 1995;Berkhout et al, 1989;Logan et al, 2004;Kilareski et al, 2009). GR, in cooperation with other regulatory proteins, can bind these sites and enhance AP-1 signaling since several AP-1 binding sites are present not only in U3, but in the U5 region of HIV-1 also.…”