br HIV Infection and the

HIV Infection and the IL-33/ST2 response: Sounding the Alarm Given that IL-33 is rapidly released from damaged BIRB 796 manufacturer following tissue damage, necrosis and activation of the inflammasome (Martin and Martin, 2016), it has been suggested that IL-33 may play a role in the pathogenesis of HIV infection (Barouch et al., 2016). In 2011, Miyagaki et al. were the first to report elevated sST2 levels in HIV-infected patients and in uninfected patients with skin barrier damage due to atopic dermatitis, compared to healthy controls (Miyagaki et al., 2011). Additionally, they observed reduced plasma levels of IL-33 in HIV-infected patients independently of the severity of their infection, in contrast to patients with atopic dermatitis. However, the dysregulated plasma levels of sST2 and of IL-33 did not correlate with age, eosinophil count or with other clinical parameters, which could be due to the small sample size of the study. In contrast, Secemsky et al. reported that 332 long-term antiretroviral therapy (ART)-treated HIV-infected patients had similar sST2 levels compared to age- and sex-matched controls (Secemsky et al., 2015). The aim of this study was to assess and to compare plasma sST2 levels with novel cardiovascular disease biomarkers such as growth differentiation factor 15 (GDF-15) and troponin I, in addition to established biomarkers such as C-reactive protein (CRP), D-dimer, IL-6 and cystatin C (Table 1). Despite non-elevated ST2 mean levels, sST2 and GDF-15 were predictors of cardiac insufficiency and of all-cause mortality in ART-treated patients, consistent with previous reports of uninfected individuals (Chen et al., 2013). Furthermore, Fitch et al. recently reported elevated ST2 levels as a marker of myocardial fibrosis in asymptomatic HIV-infected patients (Fitch et al., 2016). However, it should be noted that in both of these studiess of treated, HIV-infected individuals, single cross-sectional assessments of each biomarker were made. HIV-associated gut barrier dysfunction and immune activation, which have been observed to occur early in infection, represent independent predictors of morbidity and mortality (Ponte et al., 2016, Hunt et al., 2014). The initiation of ART during chronic infection can reduce, but not normalize, barrier dysfunction and immune activation (Ananworanich et al., 2015, Hunt et al., 2014). We and others have reported that when ART is initiated immediately following HIV infection, plasma levels of gut damage markers remain elevated, in contrast to markers of cellular activation and of inflammation, which decrease significantly (Jenabian et al., 2015, Ananworanich et al., 2015). Our prospective analysis failed to detect a significant reduction in sST2 levels in patients initiating ART during the early phase of HIV infection, while long-term treatment initiated during the chronic phase normalized sST2 levels (Mehraj et al., 2016). Importantly, we determined the alarmin contribution of the IL-33/ST2 axis to the immune response by reporting a correlation of elevated sST2 levels with the CD8 T-cell count and with T-cell activation in the absence of a correlation with the plasma viral load. Thus, the immune response following acute infection characterized by increased numbers of CD8 T-cells and increased activation of these cells was associated with elevated sST2 levels, in response to ‘the alarm’. The elevated sST2 levels correlated with indoleamine 2,3-dioxygenase enzyme activity and IFN-γ levels, both of which are implicated in Th1/Th2 regulation. Our findings in HIV-infected individuals support those reported by Baumann et al. of a murine lymphocytic choriomeningitis virus (LMCV) model in which IL-33 induced and enhanced Th-1 responses (Baumann et al., 2015). Furthermore, during acute HIV infection, sST2 levels correlated with the levels of intestinal fatty acid binding protein (I-FABP) and of sCD14, markers of gut epithelial damage and of microbial translocation, respectively. These observations establish a link between sST2 and gut tissue damage. Interestingly, these associations were lost during chronic HIV infection, suggesting a phase-dependent and transient role for the IL-33/ST2 axis in disease progression (Fig. 2). Moreover, IL-33, in conjunction with long-term TGF-β stimulation, has been shown to be associated with the development of fibrosis in a murine model of bleomycin-induced fibrosis (Li et al., 2014a). Gao et al. recently showed that in a murine model of diet-induced nonalcoholic steatohepatitis, IL-33 treatment prevented steatosis, while inducing fibrosis, in a ST2-dependent manner (Gao et al., 2016). Furthermore, in patients with either chronic obstructive pulmonary disease or with idiopathic pulmonary fibrosis, IL-33 is involved in the induction of lung fibrosis in bronchial epithelial cells via the induction of IL-6 and IL-8 (Shang et al., 2015). It is well established that during the chronic phase of HIV infection, collagen deposition in lymphoid tissues including Peyer\'s patches in the gut disrupts the T-cell zone and limits the number of resident CD4 T-cells (Schacker et al., 2005). The development of fibrosis is an important issue given that the level of lymphatic tissue collagen deposition foretells the magnitude of CD4 T-cell recovery following ART initiation. Thus, after sounding the alarm, the IL-33/ST2 axis may contribute to the development of fibrosis during the chronic phase of HIV infection (Fig. 2).