Human immunodeficiency virus type 1 (HIV) and Mycobacterium tuberculosis have become intertwined over the past few decades in a "syndemic" that exacerbates the morbidity and mortality associated with each pathogen alone. The severity of the coinfection has been extensively examined in clinical studies. The extrapolation of peripheral evidence from clinical studies has increased our basic understanding of how HIV increases susceptibility to TB. These studies have resulted in multiple hypotheses of how HIV exacerbates TB pathology through the manipulation of granulomas. Granulomas can be located in many tissues, most prominently the lungs and associated lymph nodes, and are made up of multiple immune cells that can actively contain M. tuberculosis. Granuloma-based research involving both animal models and clinical studies is needed to confirm these hypotheses, which will further our understanding of this coinfection and may lead to better treatment options. This review examines the data that support each hypothesis of how HIV manipulates TB pathology while emphasizing a need for more tissue-based experiments.
HIV-infected individuals with latent Mycobacterium tuberculosis (Mtb) infection are at significantly greater risk of reactivation tuberculosis (TB) than HIV-negative individuals with latent TB, even while CD4 T cell numbers are well preserved. Factors underlying high rates of reactivation are poorly understood and investigative tools are limited. We used cynomolgus macaques with latent TB co-infected with SIVmac251 to develop the first animal model of reactivated TB in HIV-infected humans to better explore these factors. All latent animals developed reactivated TB following SIV infection, with a variable time to reactivation (up to 11 months post-SIV). Reactivation was independent of virus load but correlated with depletion of peripheral T cells during acute SIV infection. Animals experiencing reactivation early after SIV infection (<17 weeks) had fewer CD4 T cells in the periphery and airways than animals reactivating in later phases of SIV infection. Co-infected animals had fewer T cells in involved lungs than SIV-negative animals with active TB despite similar T cell numbers in draining lymph nodes. Granulomas from these animals demonstrated histopathologic characteristics consistent with a chronically active disease process. These results suggest initial T cell depletion may strongly influence outcomes of HIV-Mtb co-infection.
Understanding the early immunologic events accompanying reactivated tuberculosis (TB) in HIV-infected individuals may yield insight into causes of reactivation and improve treatment modalities. We used the cynomolgus macaque (Macaca fascicularis) model of HIV–Mycobacterium tuberculosis coinfection to investigate the dynamics of multifunctional T cell responses and granuloma T cell phenotypes in reactivated TB. CD4+ and CD8+ T cells expressing Th1 cytokines (IFN-γ, IL-2, TNF) and Th2 cytokines (IL-4 and IL-10) were followed from latent M. tuberculosis infection to reactivation after coinfection with a pathogenic SIV. Coinfected animals experienced increased Th1 cytokine responses to M. tuberculosis Ags above the latent-response baseline 3–5 wk post-SIV infection that corresponded with peak plasma viremia. Th2 cytokine expression was not Ag specific, but strong, transient IL-4 expression was noted 4–7 wk post-SIV infection. Animals reactivating <17 wk post-SIV infection had significantly more multifunctional CD4+ T cells 3–5 wk post-SIV infection and more Th2-polarized and fewer Th0-, Th1-polarized CD8+ T cells during weeks 1–10 post-SIV infection than animals reactivating >26 wk post-SIV infection. Granuloma T cells included Th0-, Th1-, and Th2-polarized phenotypes but were particularly rich in cytolytic (CD107+) T cells. When combined with the changes in peripheral blood T cells, these factors indicate that events during acute HIV infection are likely to include distortions in proinflammatory and anti-inflammatory T cell responses within the granuloma that have significant effects on reactivation of latent TB. Moreover, it appears that mycobacteria-specific multifunctional T cells are better correlates of Ag load (i.e., disease status) than of protection.
Infection with HIV-1 greatly increases the risk of active tuberculosis (TB). Although hypotheses suggest HIV-1 disrupts Mycobacterium tuberculosis (Mtb) granuloma function, few studies have examined this directly. The objective of this study was to determine what evidence exists about the effect HIV-1 co-infection has upon Mtb granulomas. A systematic search of PubMed, Web of Science, and Medline up to 20 March 2015 was conducted, to identify studies comparing Mtb-infected tissue from HIV-1 infected and uninfected persons, or HIV-1 infected persons with stratified peripheral CD4 T cell (pCD4) counts. We summarized findings that focused on how HIV-1 changes granuloma formation, bacterial presence, cellular composition, and cytokine production. Nineteen studies with a combined sample size of 899 persons were included. Although studies frequently were limited by variable or inadequately described definitions of outcomes and analytical methods, HIV-1 was found to be associated with increased bacillary load within Mtb-infected tissue. Reductions in pCD4 counts within co-infected persons associated with both poorer granuloma formation and higher bacterial load. The high degree of heterogeneity among studies combined with experimental limitations made it difficult to conclusively support previously published and prevalent hypotheses about HIV-1/Mtb co-infection granulomas. To elucidate the validity of these hypotheses we have described areas that can be improved in future studies in order to clarify the influence HIV-1 co-infection has upon the Mtb granuloma.
Human immunodeficiency virus infection is the most common risk factor for severe forms of tuberculosis (TB), regardless of CD4 T cell count. Using a well-characterized cynomolgus macaque model of human TB, we compared radiographic, immunologic and microbiologic characteristics of early (subclinical) reactivation of latent M. tuberculosis (Mtb) infection among animals subsequently infected with simian immunodeficiency virus (SIV) or who underwent anti-CD4 depletion by a depletion antibody. CD4 depleted animals had significantly fewer CD4 T cells within granulomas compared to Mtb/SIV co-infected and Mtb-only control animals. After 2 months of treatment, subclinical reactivation occurred at similar rates among CD4 depleted (5 of 7 animals) and SIV infected animals (4 of 8 animals). However, SIV-induced reactivation was associated with more dissemination of lung granulomas that were permissive to Mtb growth resulting in greater bacterial burden within granulomas compared to CD4 depleted reactivators. Granulomas from Mtb/SIV animals displayed a more robust T cell activation profile (IFN-α, IFN-γ, TNF, IL-17, IL-2, IL-10, IL-4 and granzyme B) compared to CD4 depleted animals and controls though these effectors did not protect against reactivation or dissemination, but instead may be related to increased viral and/ or Mtb antigens. SIV replication within the granuloma was associated with reactivation, greater overall Mtb growth and reduced Mtb killing resulting in greater overall Mtb burden. These data support that SIV disrupts protective immune responses against latent Mtb infection beyond the loss of CD4 T cells, and that synergy between SIV and Mtb occurs within granulomas.
Background. Human immunodeficiency virus type 1 (HIV)–infected persons are more susceptible to tuberculosis than HIV–uninfected persons. Low peripheral CD4+ T-cell count is not the sole cause of higher susceptibility, because HIV–infected persons with a high peripheral CD4+ T-cell count and those prescribed successful antiretroviral therapy (ART) remain more prone to active tuberculosis than HIV–uninfected persons. We hypothesized that the increase in susceptibility is caused by the ability of HIV to manipulate Mycobacterium tuberculosis–associated granulomas.Methods. We examined 71 excised cervical lymph nodes (LNs) from persons with HIV and M. tuberculosis coinfection, those with HIV monoinfection, and those with M. tuberculosis monoinfection with a spectrum of peripheral CD4+ T-cell counts and ART statuses. We quantified differences in M. tuberculosis levels, HIV p24 levels, cellular response, and cytokine presence within granulomas.Results. HIV increased M. tuberculosis numbers and reduced CD4+ T-cell counts within granulomas. Peripheral CD4+ T-cell depletion correlated with granulomas that contained fewer CD4+ and CD8+ T cells, less interferon γ, more neutrophils, more interleukin 10 (IL-10), and increased M. tuberculosis numbers. M. tuberculosis numbers correlated positively with IL-10 and interferon α levels and fewer CD4+ and CD8+ T cells. ART reduced IL-10 production.Conclusions. Peripheral CD4+ T-cell depletion correlated with increased M. tuberculosis presence, increased IL-10 production, and other phenotypic changes within granulomas, demonstrating the HIV infection progressively changes these granulomas.
Background Tuberculosis ( TB ) kills millions of people every year. CD 4 and CD 8 T cells are critical in the immune response against TB . T cells expressing both CD 4 and CD 8 ( CD 4 CD 8 T cells) are functionally active and have not been examined in the context of TB . Methods We examine peripheral blood mononuclear cells ( PBMC ) and bronchoalveolar lavage cells ( BAL ) and lung granulomas from 28 cynomolgus macaques during Mycobacterium tuberculosis (Mtb) infection. Results CD 4 CD 8 T cells increase in frequency during early Mtb infection in PBMC and BAL from pre‐infection. Peripheral, airway, and lung granuloma CD 4 CD 8 T cells have distinct patterns and greater cytokine production than CD 4 or CD 8 T cells. Conclusion Our data suggest that CD 4 CD 8 T cells transient the blood and airways early during infection to reach the granulomas where they are involved directly in the host response to Mtb.
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