These results are particularly relevant in the context of
These results are particularly relevant in the context of South Africa and other TB-endemic settings, as widespread latent TB infection and the resultant elevated T-cell activation we have observed may provide an explanation for more rapid progression of HIV to AIDS and increased mortality in this setting. Additionally, repeated episodes of active TB are often seen among HIV-infected individuals in this setting (Wood et al., 2011), and the observed increase in inflammatory cytokines during these episodes may also drive an accelerated course of HIV disease. Our finding of increased T-cell activation may also provide additional support for the treatment of latent TB infection with isoniazid in HIV-infected individuals. While recent guidelines have recommended widespread treatment of LTBI (diagnosed by TST or M. tb-specific interferon gamma release assay (IGRA)) among those co-infected with HIV, actual coverage rates remain low (Young et al., 2009; Lawn et al., 2010). Our work suggests that by driving immune activation, latent TB may contribute to progression to AIDS and mortality, thereby potentially adding to the reasons for more widespread use of isoniazid preventative therapy (IPT) for those co-infected with LTBI and HIV. The ability of IPT to decrease T-cell activation associated with LTBI should be tested. The different mechanisms by which immune activation may be affected by latent and active states of TB infection remain unclear, but recent work suggests that replicating and nonreplicating bacteria may elicit different immune responses. Mariotti et al. report that while replicating M. tuberculosis is able to induce IL-1b, modulate the macrophage inflammasome, and activate T-cells, nonreplicating bacteria are able to trigger T-cell activation, but not any other inflammatory processes (Mariotti et al., 2013). This observation may partially explain why latently infected individuals display lymphocyte markers of activation, while individuals with active TB disease harboring large numbers of replicating mycobacteria have measurable buy Y-27632 and activation in both the innate and adaptive branches. Further in vitro and translational work is required to test this hypothesis, as well as to better define the metabolic activity of bacteria in HIV-infected individuals with latent TB co-infection. Because previous studies of the effect of latent or active TB on immune activation have primarily characterized HIV-uninfected individuals, and because we were specifically interested in immune activation markers implicated in HIV pathogenesis, we only assessed these markers in HIV co-infected subjects. While previous studies have found no evidence for elevated immune activation (of either bulk T-cells or M. tb-specific T-cells) in latently-infected, HIV-negative individuals (Rodrigues et al., 2002; Wergeland et al., 2011; de Almeida et al., 2012; Adekambi et al., 2012; Hodapp et al., 2012), our data suggest that this is not the case for HIV-infected individuals who also harbor latent TB infection. This surprising finding challenges the notion of latency as a fully dormant state of TB infection, and suggests that HIV co-infection may skew this heterogeneous state towards a state that immunologically resembles more active infection. Despite the rigorous definitions used to characterize individuals as latently infected, it appears that, like active TB, latent TB may be a fundamentally different immunological phenomenon in the context of HIV co-infection. In a 2009 review, Barry et al. propose a redefinition of the different stages of M. tb infection, with five different categories of disease rather than the canonical latent vs. active dichotomy (Barry et al., 2009). Taken into the context of this spectrum, the HIV+LTBI group that we describe in this study while clearly not having “clinical disease” may fall between the categories of “quiescent” and “active” infection (Barry et al., 2009). Importantly, evidence shows that integration of isoniazid preventive therapy (IPT) with ART is crucial for successful treatment of latent TB in HIV-infected individuals, further suggesting that HIV co-infection may fundamentally alter latent TB and its susceptibility to treatment (Houben et al., 2014). The development of improved diagnostic tools and imaging techniques, such as positron emission tomography-computed tomography (PET-CT) for determining an individual\'s placement along the spectrum of TB disease will allow for a more nuanced picture of TB disease, and will also facilitate a deeper understanding of the role played by HIV at different stages of TB infection (Ghesani et al., 2014).