Granulomatous Responses in HIV and Mycobacterium tuberculosis Coinfection.

How and why human immunodeficiency virus type 1 (HIV-1) infection is conducive to more-frequent activeMycobacterium tuberculosis infection worldwide remains a key health issue. Tuberculosis is one of the few HIV-1–associated infections that occurs with increased frequency within even the first year of HIV-1 infection, as elucidated clearly in a study of tuberculosis among South African gold miners [1]. The higher early risk of tuberculosis in HIV-1–infected persons, compared with uninfected healthy subjects in the community, occurs when circulating CD4 T-cell counts are still preserved. However, the risk of developing active tuberculosis rises even more substantially with advancing HIV-1 disease [2, 3]. Antiretroviral therapy (ART) results in a significant reduction in risk of developing active tuberculosis; however, it does not reduce the risk back to levels seen in HIV1–uninfected community control subjects [4, 5]. Diedrich et al, in this issue of The Journal of Infectious Diseases, explore at the tissue level M. tuberculosis–induced granulomas in persons with and those without HIV-1 infection to try to better understand some of the mechanisms of the HIV-1–induced risk of tuberculosis. The tissue granuloma is the microenvironment of control and containment of M. tuberculosis infection or lack thereof. The granuloma is a collection of immunological cells that are loosely organized and generally consists of a central necrotic area of macrophages and epithelioid cells surrounded by a lymphocyte/macrophage layer. The immunologic features of the human granulomatous response to M. tuberculosis has not been investigated in detail. Diedrich et al explore the immunopathologic and microbiologic features of tuberculosis granulomatous response in the setting of HIV-1 infection as the driver of tuberculosis, rather than as the mechanism for controlling M. tuberculosis infection. The granuloma is felt to be one of, if not the primary, sites of reactivation from latency or failure to develop latency after recent infection in what, instead, results in primary progressive disease. The granuloma is the hallmark histopathological lesion that occurs at all clinical sites of tuberculosis, including the lymph nodes, which is the focus of study by Diedrich et al, as well as the many other tissue sites, including the lung, pleura, central nervous system, bones, and peritoneum. The question they examine is whether and how HIV-1 manipulates M. tuberculosis-induced granulomas. This study investigated cervical lymph node biopsy specimens collected over 6 years and preserved as tissue blocks. All specimens were from individuals who received a diagnosis of tuberculosisassociated lymphadenitis, had clinical information available, and were from Cape Town, South Africa, where tuberculosis is endemic and the level of M. tuberculosis/ HIV coinfection is very high. Fifty-five subjects had a diagnosis of M. tuberculosis infection, of whom 70% had HIV/M. tuberculosis coinfection. Diedrich et al performed detailed immunohistochemical analysis of the tissue blocks. The key findings were that HIV-1 coinfection was correlated with increased recovery of M. tuberculosis but decreased CD4 T-cell counts in the granulomas. Peripheral CD4 T-cell depletion was correlated with fewer T cells, fewer interferon γ (IFN-γ)– producing cells in the granulomas, but increases in neutrophil counts, interleukin 10 (IL-10) levels, and M. tuberculosis levels. The subgroup receiving antiretroviral therapy (ART) had reduced IL-10 production in the granulomas. The overall conclusion reached by Diedrich et al is not surprising: HIV-1 infection progressively altersM. tuberculosis– induced granulomas. The aspects of their findings that are more novel include the extensive CD15 staining in the granuloma; CD15 is generally considered a neutrophil marker. They did not see intact neutrophils, so they felt it was likely neutrophil debris that they were observing. If this is a correct assumption, the neutrophils are likely recruited to the site and die quickly. They speculate that the neutrophils are the source of the IL-10, which was the dominant cytokine in the caseum of the granulomas, whereas tumor necrosis factor α (TNF-α) and IFN-γ were the dominant cytokines in the T cell– and macrophage–rich periphery of the Received and accepted 19 July 2016; published online 26 July 2016. Correspondence: D. H. Canaday, 10900 Euclid Ave, BRB 10th flr, Cleveland, OH 44106-4984 (dxc44@case.edu). The Journal of Infectious Diseases 2016;214:1292–3 © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com. DOI: 10.1093/infdis/jiw314