HIV, SIV, Tuberculosis, T cells, Macrophages (See the Major Article by Kuroda et al, on pages 1865–74.) Clinical studies have provided compelling evidence that people coinfected with human immunodeficiency virus (HIV) and Mycobacterium tuberculosis have a 20–30-fold higher risk of developing active tuberculosis as compared to individuals with M. tuberculosis monoinfection . Considering the critical role of T cells in preventing tuberculosis dissemination and the reduction of CD4+ T cells in HIV-positive patients, it was anticipated that the number of circulating CD4+ T cells should be directly linked to prevention or reactivation of latent M. tuberculosis infection. However, the risk of developing active tuberculosis is significantly increased during the early phase of HIV infection  or after antiretroviral therapy , conditions in which CD4+ T-cell counts may be within the normal range. These data indicate that the decline in the number of CD4+ T cells in HIV-infected individuals may not be solely responsible for the progression from latent M. tuberculosis infection to active tuberculosis [2–4]. In this issue of The Journal of Infectious Diseases, Kuroda et al provide evidence for the engagement of specific innate immune compartments, independent of T cells, to ignite active tuberculosis in the simian immunodeficiency virus (SIV) infection model of rhesus macaques. This important study has both biological and clinical translational implications. In the past few years, innate immune cells, particularly monocytes and macrophages, have received considerable attention in the field of HIV research. Initially, Hasegawa et al elegantly showed that, in SIV-infected rhesus macaques, macrophage death led to high monocyte turnover and positively correlated with the progression to AIDS and increased mortality . Several recent studies have supported this observation and demonstrated that, in SIV-infected rhesus macaques, increased monocyte turnover is directly associated with progression to AIDS and lung tissue damage, independent of CD4+ T cell count and viral load [6, 7]. Additionally, it was shown that HIV infects human alveolar macrophages, which impairs their antimicrobial capacity , and that coinfection of human macrophages with HIV and M. tuberculosis in vitro significantly increases cell death . Considering the essential role of macrophages in protection against M. tuberculosis, the increased turnover of circulatory monocytes might be a signature of impaired pulmonary macrophages in individuals with tuberculosis and HIV infection. The study by Kuroda et al addresses this possibility and shows that the enhanced turnover of blood monocytes (assessed by BrdU labeling) is directly linked to reactivation of latent M. tuberculosis infection in rhesus macaques coinfected with SIV and M. tuberculosis. Importantly, the SIV-dependent decline of circulating CD4+ T cells was similar between animals presenting with latent M. tuberculosis infection and those with active tuberculosis. Thus, reactivation of latent M. tuberculosis infection cannot simply be attributed to a change in the T-cell response. To build their case, the authors also examined the number of coinfected pulmonary cells and determined that the majority were macrophages. Additionally, they observed that only in animals with reactivation of latent M. tuberculosis in SIV coinfection were the levels of pulmonary SIV DNA significantly increased. These findings raise the question of how pulmonary macrophages are simultaneously infected by M. tuberculosis and SIV. Are these macrophages initially infected with M. tuberculosis and then SIV, or vice versa? If alveolar macrophages can be infected by HIV and, therefore, become impaired in controlling M. tuberculosis, then the increased frequency of active tuberculosis among HIV-infected patients might be also due to inadequate initial control of tuberculosis in such individuals. However, of note, we still do not know exactly how M. tuberculosis translocates from the alveolar space into the lung parenchyma tissues and leads to granuloma formation. The study by Kuroda et al also raises new questions about the specific signaling that regulates monopoiesis in the bone marrow. For instance, under steady-state conditions, myeloid cell growth factors (eg, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and macrophage colony-stimulating factor) are essential for the generation of monocytes in the bone marrow. By contrast, the increased production of monocytes during infection/inflammation is mainly mediated by pattern-recognition receptors and cytokines, including type I and type II interferons (IFNs) [10–12]. Furthermore, mobilization of inflammatory monocytes from the bone marrow is mediated by the expression of chemokine receptor CCR2 that recognizes monocyte chemoattractant protein 1 (MCP1) and MCP3 ligands, which are mainly produced by macrophages . Thus, in the current study, it is not clear that the augmented number of circulating monocytes is a consequence of increased production of MCP1/MCP3 in the lungs or an increase of danger signals produced by dead macrophages coinfected with M. tuberculosis and SIV. It is also important to understand the quality of monocytes that are mobilized from bone marrow into the blood and ultimately the lung. Sher’s group has previously demonstrated that increased pulmonary production of type I IFN in M. tuberculosis–infected mice promotes the CCR2-dependent recruitment of a myeloid cell population (CD11b+F4/80+Gr1int) that is uniquely permissive for M. tuberculosis infection . Consistent with this study, SIV-induced production of type I IFN in coinfected individuals may increase the proliferation and/or differentiation of hematopoietic stem and progenitor cells into permissive monocytes/macrophages that benefits the pathogen rather than the host. Therefore, further investigation is required to unravel the role of monocytes in the reactivation of latent M. tuberculosis infection. When a host encounters a new pathogen, the immune system either generates an early response to eliminate the pathogen, an overwhelming response that jeopardizes host survival, or a persistent response that allows both host and pathogen to live. Although M. tuberculosis is one of the most successful human pathogens, infection in 90%–95% of individuals with M. tuberculosis is latent and thereby asymptomatic and nontransmissible . This indicates that, through a long evolutionary process between the host and M. tuberculosis, an equilibrium is reached that supports both host and bacterial survival. Similarly, sooty mangabeys and African green monkeys are the natural hosts for SIV and fail to develop a robust antiviral response and disease despite high levels of viremia . In addition, a recent study of HIV infection in pediatric patients demonstrated that a subset of HIV-infected children who did not received antiretroviral therapy exhibited high viremia levels yet remained disease free and clinically healthy . Interestingly, these children with nonprogressing HIV infection demonstrated minimal immune activation and maintained normal CD4+ T-cell counts . Thus, the major cause of transition from HIV to AIDS or inactive to active tuberculosis in humans may not be dictated by the pathogen load but, rather, the dysregulated immune response to infections [18, 19]. Finally, the findings by Kuroda et al have implications for understanding the cellular mechanisms mediating immune activation during M. tuberculosis–SIV coinfection in nonhuman primates. The authors have provided important insights into how expansion of monocytes/macrophages in the demanding environment of the lung coinfected with M. tuberculosis and SIV may change the equilibrium of host-pathogen interactions, resulting in detrimental effects on the host. Undoubtedly, more research will be needed to identify the exact cellular and molecular mechanisms involved in the altered immune activation that significantly compromises host fitness and disease tolerance during tuberculosis and HIV infection. Note Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Getahun H , Gunneberg C , Granich R , Nunn P . HIV infection-associated tuberculosis: the epidemiology and the response . Clin Infect Dis 2010 ; 50 ( Suppl 3 ): S201 – 7 . Google Scholar CrossRef Search ADS PubMed 2. Walker NF , Meintjes G , Wilkinson RJ . HIV-1 and the immune response to TB . Future Virol 2013 ; 8 : 57 – 80 . Google Scholar CrossRef Search ADS PubMed 3. Lawn SD , Myer L , Edwards D , Bekker LG , Wood R . Short-term and long-term risk of tuberculosis associated with CD4 cell recovery during antiretroviral therapy in South Africa . AIDS 2009 ; 23 : 1717 – 25 . Google Scholar CrossRef Search ADS PubMed 4. Sonnenberg P , Murray J , Glynn JR , Shearer S , Kambashi B , Godfrey-Faussett P . 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Mucosal Immunol 2014 ; 7 : 1116 – 26 . Google Scholar CrossRef Search ADS PubMed 9. Pathak S , Wentzel-Larsen T , Asjö B . Effects of in vitro HIV-1 infection on mycobacterial growth in peripheral blood monocyte-derived macrophages . Infect Immun 2010 ; 78 : 4022 – 32 . Google Scholar CrossRef Search ADS PubMed 10. Lieschke GJ , Grail D , Hodgson G , et al. Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization . Blood 1994 ; 84 : 1737 – 46 . Google Scholar PubMed 11. Buechler MB , Teal TH , Elkon KB , Hamerman JA . Cutting edge: Type I IFN drives emergency myelopoiesis and peripheral myeloid expansion during chronic TLR7 signaling . J Immunol 2013 ; 190 : 886 – 91 . Google Scholar CrossRef Search ADS PubMed 12. de Bruin AM , Libregts SF , Valkhof M , Boon L , Touw IP , Nolte MA . IFNγ induces monopoiesis and inhibits neutrophil development during inflammation . 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This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
The Journal of Infectious Diseases – Oxford University Press
Published: Feb 8, 2018
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