This study reports that HIV infection is associated with a profound dysregulation in the expression of genes encoding for members of the nuclear receptor super family in circulating monocytes.
It is well known HIV infection is associated to a chronic inflammatory condition and lipid abnormalities, with the latter being a consequence or concurrent cause of the inflammation state. Moreover, in treated patients, in spite of an effective control of the viral replication as well as in absence of pharmaco-induced dyslipidemias, a residual persistent chronic inflammatory status, which can limit the long-term effectiveness of therapy, can be detected .
We now provide evidence that, during the course of HIV infection, the expression of a large group of nuclear receptors is dramatically reset in monocytes, that this resetting is associated to a robust activation of circulating monocytes as demonstrated by 10–20 fold increase in the monocytic expression of MCP-1- RNA, and that HAART is not able to revert all the observed alterations. Specifically, we have obtained evidence that HIV infection causes profound down-regulations for FXR, PXR, PPARα, GR, RARα and RXRα. These down regulations were also observed under effective HAART.
A common motif of these transcription factors is their ability to activate counter-regulatory signals essential to reduce inflammation [7, 8]. Indeed, besides the canonical anti-inflammatory activity of GR, FXR, PXR, PPARα, RARα and RXRα attenuate the inflammatory responses and their activations reduce immune dysfunction-driven inflammation in a variety of experimental and clinical settings [7, 13]. Furthermore, data from a variety of gene deficient mice strongly supports the general notion that ablation of these receptors leads to the development of a deregulated immunity and causes metabolic dysfunction [7, 13]. The present study is, therefore, a general model to examine the effect of viral infection and to further understand how HIV virus-induced inflammation and immune-dysfunction progress in human disease.
The detected alterations in the nuclear receptor expression are probably an indirect effect of viral replication, considering that only a very low number of circulating monocytes is infected by HIV . These changes could be determined by either the chronic inflammatory process, as seen in atherosclerosis, type 2 diabetes mellitus, intestinal chronic inflammation, including inflammation driven gastrointestinal cancers, or the residual immune activation and microbial translocation associated with increased levels of LPS [15–20]. This could also arise from the action of some HIV proteins that can persist for a long time- in the body of virologically controlled patients . This latter hypothesis could explain the persistent alterations observed in the group of HAART-treated HIV-positive subjects. Indeed, recently we have documented that the p17 HIV protein, which can persist in lymph nodes germinal centers of patients effectively treated , was able to down regulate PPARγ and FXR expressions in both THP1 cells and in healthy donors monocytes. Moreover, the serum from HIV+ patients containing high levels of anti p17 antibodies was able to revert the down regulation of PPARγ and FXR in their monocytes .
Thereby, this implicates that the reset expressions of nuclear receptors, which are counter-inflammatory in nature, are likely instrumental in the progression of viral infection and the persistence of a chronic inflammatory state. Noteworthy, it has been demonstrated that members of nuclear receptor superfamily (i.e. GR, FXR, PXR, RAR and RXR) regulate immune responses and a proinflammatory state with the so called transrepression pathway, able to inhibit NF-KB . It remains unclear whether the observed changes are causes or consequences of the characteristic inflammatory profile in HIV and whether NRs agonists can directly suppress residual inflammation.
In addition to their role in regulating immune responses, nuclear receptors regulate glucose and lipid metabolism . Indeed, FXR has been demonstrated to regulate insulin secretion and sensitivity and FXR ligands reduce lipid and glucose levels in murine models of diabetes [23, 24]. Similar beneficial effects on glucose metabolism have been shown for PXR , as well as for the fibrates (PPARα agonists) that are widely used for treatment of dyslipidemic conditions . In short, abrogation of the expression of these genes might provide an explanation for immune dysfunction and dyslipidemia observed in HIV disease. Importantly, it has been demonstrated that FXR activation results in a slight reduction of HDL and in an induction of LDL , and therefore its abrogation might also provide some explanation for the hypo-cholesterolemia observed in HIV-positive persons.
Another important observation we made was that two nuclear receptors, VDR and PPARβ, appeared robustly induced in monocytes of HIV-infected patients. In addition, while the expressions of VDR and PPARβ normalize, the expression of LXR becomes significantly induced under HAART. This is an important observation, as a common side effect of LXR activation is hyper-triglyceridemia , and therefore its induction might provide a further explanation of the hyper-triglyceridemia observed in HAART.
In this study we have also seen that monocyte expression of CD36, whose transcription is primarily regulated by LXR, PPARγ and PXR, is markedly reduced by HIV infection. This suggests that the transcription of this gene is impaired in HIV monocytes. Noteworthy, we found the mRNA levels of CD36 significantly correlated with those of PPARγ in only HIV positive patients, thus providing a prognostic/diagnostic value to our profiles. Indeed, it has been previously demonstrated that HIV infection results in substantial decreases in serum total cholesterol, HDL and LDL levels and that subsequent HAART initiation is associated with increases in total cholesterol and LDL but little change in HDL . Furthermore, patients with CD36 deficiency show increased levels of chylomicron remnants and small dense low-density lipoprotein (sdLDL) particles . Thus, the reduction of CD36 gene expression we reported in this study might contribute to the high levels of total cholesterol in HIV positive persons taking HAART. These results also highlight a potential therapeutic role for PPARγ agonists in treating HIV associated dyslipidemia.