Mycobacteria‐infected bystander macrophages trigger maturation of dendritic cells and enhance their ability to mediate HIV transinfection

Abstract

Synergistic interplay between Mycobacterium tuberculosis (Mtb) and HIV in coinfected individuals leads to the acceleration of both tuberculosis and HIV disease. Mtb, as well as HIV, may modulate the function of many immune cells, including DCs. To dissect the bystander impact of Mφs infected withMtb on DC functionality, we here investigated changes in DC phenotype, cytokine profiles, and HIV-1 transinfecting ability. An in vitro system was used in which human monocyte-derived DCs were exposed to soluble factors released by Mφs infected with mycobacteria, including virulent clinical Mtb isolates and nonvirulent BCG. Soluble factors secreted from Mtb-infected Mφs, and to a lesser extent BCG-infected Mφs, resulted in the production of proinflammatory cytokines and partial upregulation of DC maturation markers. Interestingly, the HIV-1 transinfecting ability of DCs was enhanced upon exposure to soluble factors released by Mtb-infected Mφs. In summary, our study shows that DCs exposed to soluble factors released by mycobacteriainfected Mφs undergo maturation and display an augmented ability to transmit HIV-1 in trans. These findings highlight the important role of bystander effects during the course of Mtb-HIV coinfection and suggest that Mtb-infected Mφs may contribute to an environment that supports DC-mediated spread and amplification of HIV in coinfected individuals. Keywords: coinfection · dendritic cell · HIV-1 · macrophage · Mycobacterium tuberculosis Supporting Information available online IntroductionTuberculosis (TB) remains the leading cause of death among HIV-infected patients, accounting for about 26% of AIDS-related deaths [1]. Unlike other opportunistic infections affecting severely immunocompromised patients, active TB can develop throughout Correspondence: Dr. Jolanta Mazurek e-mail: Jolanta.Mazurek@ki.se the entire course of HIV infection. Pulmonary TB is often diagnosed in people with relatively intact immune systems, whereas extrapulmonary TB is seen more frequently in AIDS patients (CD4 < 200/mm 3 ) [2]. In principle, Mycobacterium tuberculosis (Mtb), which causes TB, can infect any organ in the body, but lymph nodes are the most common location for extrapulmonary TB [3]. * These authors contributed equally to this work.C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2012. 42: 1192-1202 Immunity to infection 1193The interplay between Mtb and HIV is two sided and synergistic. HIV infection contributes strongly to the reactivation of latent Mtb infection and progression to active TB. Thus, the lifetime risk of developing active TB in immunocompetent adults is estimated to be 5-10%, while this risk is increased to 5-15% annually in HIV-positive individuals [4]. In addition, Mtb infection severely dysregulates immune homeostasis of the host. Mycobacterial antigens enhance cytokine and chemokine production in blood [5] and elevated levels of proinflammatory cytokines in plasma are observed during pleural TB [6]. TB status is also reflected in the circulation by a ...

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