Immune reconstitution inflammatory syndrome (IRIS) is a considerable problem in the treatment of HIV-infected patients. To identify immunologic correlates of IRIS, we characterized T-cell phenotypic markers and serum cytokine levels in HIV patients with a range of different AIDS-defining illnesses, before and at regular time points after initiation of antiretroviral therapy. Patients developing IRIS episodes displayed higher frequencies of effector memory, PD-1 ؉ , HLA-DR ؉ , and Ki67 ؉ CD4 ؉ T cells than patients without IRIS. Moreover, PD-1 ؉ CD4 ؉ T cells in IRIS patients expressed increased levels of LAG-3, CTLA-4, and ICOS and had a Th1/Th17 skewed cytokine profile upon polyclonal stimulation. Elevated PD-1 and Ki67 expression was also seen in regulatory T cells of IRIS patients. Furthermore, IRIS patients displayed higher serum interferon-␥, compared with non-IRIS patients, near the time of their IRIS events and higher serum interleukin-7 levels, suggesting that the T-cell populations are also exposed to augmented homeostatic signals. In conclusion, our findings indicate that IRIS appears to be a predominantly CD4-mediated phenomenon with reconstituting effector and regulatory T cells showing evidence of increased activation from antigenic exposure. These studies are registered online at http://clinicaltrials. gov as NCT00557570 and NCT00286767. (Blood. 2010;116(19):3818-3827) IntroductionImmune reconstitution inflammatory syndrome (IRIS) is a term used to describe the paradoxical worsening or unmasking of infections or tumors after antiretroviral therapy (ART) initiation. 1 Two clinical predictors for the development of IRIS have been identified in clinical studies: severe CD4 ϩ T-cell lymphopenia before ART initiation and the presence of opportunistic diseases either symptomatic (paradoxical IRIS) or occult (unmasking IRIS). 2,3 Some studies have also shown a significant association between shorter duration of treatment of underlying infection and ART initiation with paradoxical IRIS. 3 Although a high proportion of IRIS events are related to underlying mycobacterial diseases (eg, Mycobacterium tuberculosis and M avium complex), 4 a variety of other opportunistic infections and AIDS-associated conditions have also been identified as predisposing factors.The pathogenesis of IRIS is still unclear. The best evidence comes from studies suggesting an exuberant Th1 response and increased proportions of killer inhibitory receptor (KIR) Ϫ ␥␦ ϩ T cells post-ART in patients with tuberculosis (TB)-IRIS, compared with patients with TB, but no IRIS event. 5,6 Subsequent studies, though, did not show a clear association of TB-IRIS, with more pronounced restoration of Th1 pathogen-specific response for TB. 7 The possibility of a lack of appropriate regulatory T-cell (Treg) response because of inadequate numbers of Treg has also been investigated. Phenotypic studies examining Treg frequency in peripheral blood have showed similar proportions of these cells in patients who developed TB-IRIS and those who did not. 7 Anoth...

Over the past 20 years, the ability of the xenobiotic receptors to coordinate an array of drug-metabolizing enzymes and transporters in response to endogenous and exogenous stimuli has been extensively characterized and well documented. The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are the xenobiotic receptors that have received the most attention since they regulate the expression of numerous proteins important to drug metabolism and clearance and formulate a central defensive mechanism to protect the body against xenobiotic challenges. However, accumulating evidence has shown that these xenobiotic sensors also control many cellular processes outside of their traditional realms of xenobiotic metabolism and disposition, including physiologic and/or pathophysiologic responses in energy homeostasis, cell proliferation, inflammation, tissue injury and repair, immune response, and cancer development. This review will highlight recent advances in studying the noncanonical functions of xenobiotic receptors with a particular focus placed on the roles of CAR and PXR in energy homeostasis and cancer development.

The gut mucosa is an important site of HIV immunopathogenesis, with severe depletion of CD4+ T cells occurring during acute infection. The effect of prolonged anti-retroviral therapy (ART) on cycling and restoration of T lymphocytes in the gut remains unclear. Colon and terminal ileal biopsies and peripheral blood samples were collected from viremic, untreated, HIV-infected participants, patients treated with prolonged ART (>5 years), and uninfected controls and analyzed by flow cytometry. In the gut, the proportion of cycling T cells decreased and the number of CD4+ T cells normalized in treated patients in parallel with β7 expression on CD4+ T cells in blood. Cycling of gut T cells in viremic patients was associated with increased plasma LPS levels, but not colonic HIV-RNA. These data suggest that gut T cell activation and microbial translocation may be interconnected while prolonged ART may decrease activation and restore gut CD4+ T cells.

During acute human immunodeficiency virus (HIV) infection, there is a massive depletion of CD4؉ T cells in the gut mucosa that can be reversed to various degrees with antiretroviral therapy. -infected individuals treated with prolonged antiretroviral therapy (ART) (VL [viral load]<50). We found that LTNPs have intact CD4؉ T cell populations, including Th17 and cycling subsets, in the gut mucosa and a preserved T cell population expressing gut homing molecules in the peripheral blood. In addition, we observed no evidence of higher monocyte activation in LTNPs than in HIV-infected (HIV ؊ ) controls. These data suggest that, similar to nonpathogenic simian immunodeficiency virus (SIV) infection, LTNPs preserve the balance of CD4 ؉ T cell populations in blood and gut mucosa, which may contribute to the lack of disease progression observed in these patients.