HIV and the tuberculosis "set point": how HIV impairs alveolar macrophage responses to tuberculosis and sets the stage for progressive disease

Abstract

As HIV has fueled a global resurgence of tuberculosis over the last several decades, there is a growing awareness that HIV-mediated impairments in both innate and adaptive immunity contribute to the heightened risk of tuberculosis in people with HIV. Since early immune responses to Mycobacterium tuberculosis (Mtb) set the stage for subsequent control or progression to active tuberculosis disease, early host-pathogen interactions following Mtb infection can be thought of as establishing a mycobacterial "set point," which we define as the mycobacterial burden at the point of adaptive immune activation. This early immune response is impaired in the context of HIV coinfection, allowing for a higher mycobacterial set point and greater likelihood of progression to active disease with greater bacterial burden. Alveolar macrophages, as the first cells to encounter Mtb in the lungs, play a critical role in containing Mtb growth and establishing the mycobacterial set point. However, a number of key macrophage functions, ranging from pathogen recognition and uptake to phagocytosis and microbial killing, are blunted in HIV coinfection. To date, research evaluating the effects of HIV on the alveolar macrophage response to Mtb has been relatively limited, particularly with regard to the critical early events that help to dictate the mycobacterial set point. A greater understanding of alveolar macrophage functions impacted by HIV coinfection will improve our understanding of protective immunity to Mtb and may reveal novel pathways amenable to intervention to improve both early immune control of Mtb and clinical outcomes for the millions of people worldwide infected with HIV.

Keywords: Coinfection; HIV; Innate immunity; Macrophages; Tuberculosis.

Fig. 1

Graphical depiction of the mycobacterial set point as a theoretical construct, represented as the Mycobacterium tuberculosis (Mtb) bacterial burden after infection, either alone or in the context of HIV coinfection. After infection, Mtb bacterial burden increases until adaptive immunity is activated, thereby establishing the mycobacterial set point. Alveolar macrophages, the first cells to encounter Mtb, are an important component of the early innate immune response to Mtb. As reviewed in the main text, the mycobacterial burden at the point of adaptive immune activation plays a important role in the subsequent control of infection and progression to active tuberculosis disease. In the case of HIV coinfection, impairments in alveolar macrophage functions lead to poor early immune control of Mtb which, in turn, leads to a higher mycobacterial set point and greater Mtb bacterial burden at the time when adaptive immunity is activated

Fig. 2

The balance of alveolar macrophage polarization and activity. Early Mtb killing and control leads to a lower mycobacterial set point, whereas early Mtb growth and dissemination lead to a higher mycobacterial set point. HIV infection favors early Mtb growth and dissemination and a higher mycobacterial set point

Fig. 3

Events in alveolar macrophage uptake and response to Mtb infection that are impacted by HIV coinfection. (1) Recognition: HIV coinfection downregulates alveolar macrophage expression of Mtb recognition receptors including mannose and toll-like receptors. (2) Uptake and phagocytosis: HIV coinfection impairs phagocytosis. (3) Phagolysosomal fusion: HIV coinfection disrupts endosomal trafficking and impairs phagolysosomal maturation. (4) Antigen presentation: HIV coinfection leads to the expression of immature MHC class II complexes and thereby impairs the activation of adaptive immune responses. (5) Activation of adaptive immunity: HIV coinfection reduces the expression of costimulatory molecules for activation of adaptive immunity. The net effect of these HIV-mediated impairments is to enable increased intracellular and extracellular Mtb growth which ultimately leads to a higher mycobacterial set point