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    • In this study we investigated changes in

    2018-10-30

    In this study, we investigated changes in MMP concentrations on ART and the association between these changes and paradoxical TB-IRIS in a well-characterized cohort of HIV-infected adults with advanced HIV/TB (Ravimohan et al. 2013; Ravimohan et al. 2015a). Furthermore, in a subset of patients, we explored the relationship between the magnitude of early immune restoration and MMP concentrations on ART and pulmonary function after TB treatment completion. We specifically selected MMP-1, -2, -3, -8, and -9 for analysis, as they have previously been found to be associated with lung tissue damage in TB (Elkington et al. 2011; Walker et al. 2012; Elkington et al. 2005; Elkington and Friedland 2006; Ong et al. 2015).
    Materials and Methods
    Results
    Discussion In this study we investigated circulating concentrations of key MMPs before and soon after ART initiation among a relatively large cohort of advanced HIV-infected patients concurrently treated for active pTB. While there was substantial heterogeneity in early MMP changes, concentrations of MMP-8 and -9 increased significantly on ART and greater early MMP-8 increases were associated with both TB-IRIS and decreased lung function months after TB cure, a time when TB-associated lung damage has typically stabilized (Hnizdo et al. 2000). Similarly, rapid increases in the CD4 count early after ART were also associated with worse lung function after TB treatment completion. These findings, combined with data that MMPs and cellular immune responses are key to granuloma and cavity formation in TB (Salgame 2011; Dutta and Karakousis 2014), support a Silvestrol manufacturer where early changes in immune function and relevant tissue proteases Silvestrol manufacturer following ART initiation contribute to long-term pulmonary function deficits post-TB cure in HIV/TB. Our data also indicate that patients with clinically apparent inflammatory events, such as those with TB-IRIS, may be especially at risk. Previous work has indicated that MMPs degrade lung collagen matrix and mediate lung tissue destruction in TB (Ong et al. 2014; Elkington et al. 2011; Elkington and Friedland 2006; Ong et al. 2015). Thus, our finding that systemic concentrations of MMP-8 and MMP-9 increase rapidly following ART initiation, as well as the association between increases in MMP-8 and TB-IRIS, which is frequently characterized by respiratory complaints (Meintjes et al. 2008; Naidoo et al. 2012; Luetkemeyer et al. 2014), suggest that HIV-infected patients with active pulmonary TB may be at risk for incident immune-mediated lung damage after ART initiation. While a somewhat consistent relationship emerged with MMP-8 and outcomes in this study, it is notable that concentrations of MMP-1, -2, and -3, which have also been implicated in lung tissue destruction (Ong et al. 2014; Elkington et al. 2011; Elkington and Friedland 2006), decreased or remained unchanged on ART. One possibility is that MMP-1 and -2 have highly compartmentalized expression at the site of infection, as demonstrated in a study of pleural tuberculosis (Hoheisel et al. 2001). Furthermore, another study showed that rifampicin can downregulate MMP-3 expression in vitro, which may explain decreases in circulating concentrations of MMP-3 in our patients, all of whom were on this drug (Singh et al. 2014). Our results are broadly consistent with a cross-sectional study of MMPs in paradoxical TB-IRIS by Tadokera et al., where concentration of MMP-7 in MTB-stimulated PBMC culture supernatants and serum were significantly higher in those with TB-IRIS (n=22) compared to non-IRIS controls (n=22) (Tadokera et al. 2014). The Tadokera study did not find an association between MMP-8 and IRIS when assessing MTB-stimulated PBMCs (Tadokera et al. 2014); however, this may relate to the fact that MMP-8 is predominantly secreted by neutrophils (Hasty et al. 1986; Parks et al. 2004), which are lost during the PBMC isolation process. MMP concentrations are highly dynamic during TB treatment (Ugarte-Gil et al. 2013), and therefore differences between the two studies may also relate to the fact that patients in the Tadokera study had a substantially longer time to ART initiation after starting TB treatment than those included here (56 versus 28days), whereas time to TB-IRIS was markedly shorter (14 versus 28days) (Tadokera et al. 2014). Our relatively large population of nearly 150 patients with advanced HIV/TB and the consistent association between changes in MMP-8 concentrations and both TB-IRIS and lung function suggest a compelling role for MMP-8 recovery in inflammatory events and tissue damage on ART that should be investigated in further detail. Taken together, the two studies indicate that additional research on the pathogenesis of tissue damage in patients with HIV/TB initiating ART is needed.