**5. Immunology of TB/HIV coinfection**

#### **5.1. HIV impact on TB infection**

TB is the leading opportunistic infection and major cause of death in HIV-seropositive people. There is some evidence that both HIV-negative and HIV-positive persons have the same chance to be infected with TB [49]. In contrast, other studies have found that already existing HIV infection increased the risk of newly acquired TB [50, 51] and relapse of dormant *M. tubercu‐ losis* [52]. However, there is unanimity that HIV exacerbates TB progress and accelerates the fatal end in coinfected individuals.

Existing data outlines two main hypotheses how HIV influences the course of TB infection: 1. HIV manipulates bactericidal activity of macrophages against *M*. *tuberculosis*; and 2. HIV kills CD4+ T cells within granulomas and facilitates *M*. *tuberculosis* survival and dissemination.

HIV impairs macrophages in HIV-positive patients turning them more susceptible to *M. tuberculosis* invasion [53]. First, HIV upregulates some of *M. tuberculosis* receptors on macro‐ phages to favor tubercle bacilli entering into the cell [54]. Second, HIV modulates oxidative stress-dependent bactericidal activity in monocytes by diminishing their capacity to produce ROS [55]. As a result of increased levels of IL-10 (an anti-inflammatory interleukin) and decreased TNF-alpha production, infected macrophages escape apoptosis [53, 56]. Thus, more macrophages are directed towards necrosis, a mechanism that increases the *M. tuberculosis* survival and dissemination in the lungs and other extra pulmonary locations. Furthermore, HIV alters the acidification of phagosomes in *M*. *tuberculosis*-infected macrophages [57], changing the rate of tubercle bacilli elimination.

HIV manifests its presence by gradual depletion of CD4+ T cells, a main feature of HIV infection and clinical sign for progression towards AIDS. The low CD4+ cell count makes the host more susceptible to tubercle bacilli as the immune system cannot establish an efficient cell-mediated immune response. The risk of reactivation of latent TB, acquirement of new TB infection, and/ or of dissemination of TB towards extra pulmonary locations increases with the decrease of CD4+ cell count; patients with CD4+ counts >350 cells/µL have unaltered clinical and radio‐ graphic presentation as HIV seronegative patients, while patients with CD4+ counts <350 cells/ µL have atypical chest X-ray findings and frequent extra pulmonary TB. HIV-positive patients in South Africa with CD4+ counts <200 cells/µL are more susceptible to *M. tuberculosis*infection than HIV-positive individuals with CD4+ counts >500 cells/µL regardless of antiretroviral therapy applied [58].

The insufficient CD4+ T number fails to control granuloma formation and maintenance, therefore leading to higher incidence of extra pulmonary TB and enlarged risk of reactivation of latent infection in HIV-positive patients. Caseous necrotic granulomas—typical for single TB infection—are rare in TB/HIV coinfected patients. Despite the same number of granulomas and acid-fast stained bacilli in TB infected and TB/HIV coinfected persons [59], granulomas from dual-infected individuals are easy disrupted and infection can readily disseminate into multiple organs to form diffuse lesions [60].

However, HIV influence on TB course may only partially depend on CD4+ depletion, as HIVpositive miners in South Africa had an increased risk (2 to 3 times higher) of developing active TB in the first and second year after HIV seroconversion, when the number of CD4+ T-cell was still high [61]. HIV-positive individuals with preserved CD4+ T cell counts (during an antiretroviral treatment) also have an increased risk of developing TB infection. This suggests that additional immunological changes could happen during HIV infection, making the host more susceptible to TB. Such possible mechanism is the observed uniform distribution of CD8+ T cells within the granuloma, in contrast to the peripheral findings in the single TB infection [62]. HIV also specifically diminishes production of IFN-gamma, IL-2, and IL-12 [63], and suppresses proliferation of TB-specific T cells. Several months after HIV seroconversion, the number of *M. tuberculosis* specific CD4+ memory cells decreases significantly [64].

#### **5.2. TB importance in HIV infection**

**5. Immunology of TB/HIV coinfection**

changing the rate of tubercle bacilli elimination.

multiple organs to form diffuse lesions [60].

therapy applied [58].

TB is the leading opportunistic infection and major cause of death in HIV-seropositive people. There is some evidence that both HIV-negative and HIV-positive persons have the same chance to be infected with TB [49]. In contrast, other studies have found that already existing HIV infection increased the risk of newly acquired TB [50, 51] and relapse of dormant *M. tubercu‐ losis* [52]. However, there is unanimity that HIV exacerbates TB progress and accelerates the

Existing data outlines two main hypotheses how HIV influences the course of TB infection: 1. HIV manipulates bactericidal activity of macrophages against *M*. *tuberculosis*; and 2. HIV kills CD4+ T cells within granulomas and facilitates *M*. *tuberculosis* survival and dissemination.

HIV impairs macrophages in HIV-positive patients turning them more susceptible to *M. tuberculosis* invasion [53]. First, HIV upregulates some of *M. tuberculosis* receptors on macro‐ phages to favor tubercle bacilli entering into the cell [54]. Second, HIV modulates oxidative stress-dependent bactericidal activity in monocytes by diminishing their capacity to produce ROS [55]. As a result of increased levels of IL-10 (an anti-inflammatory interleukin) and decreased TNF-alpha production, infected macrophages escape apoptosis [53, 56]. Thus, more macrophages are directed towards necrosis, a mechanism that increases the *M. tuberculosis* survival and dissemination in the lungs and other extra pulmonary locations. Furthermore, HIV alters the acidification of phagosomes in *M*. *tuberculosis*-infected macrophages [57],

HIV manifests its presence by gradual depletion of CD4+ T cells, a main feature of HIV infection and clinical sign for progression towards AIDS. The low CD4+ cell count makes the host more susceptible to tubercle bacilli as the immune system cannot establish an efficient cell-mediated immune response. The risk of reactivation of latent TB, acquirement of new TB infection, and/ or of dissemination of TB towards extra pulmonary locations increases with the decrease of CD4+ cell count; patients with CD4+ counts >350 cells/µL have unaltered clinical and radio‐ graphic presentation as HIV seronegative patients, while patients with CD4+ counts <350 cells/ µL have atypical chest X-ray findings and frequent extra pulmonary TB. HIV-positive patients in South Africa with CD4+ counts <200 cells/µL are more susceptible to *M. tuberculosis*infection than HIV-positive individuals with CD4+ counts >500 cells/µL regardless of antiretroviral

The insufficient CD4+ T number fails to control granuloma formation and maintenance, therefore leading to higher incidence of extra pulmonary TB and enlarged risk of reactivation of latent infection in HIV-positive patients. Caseous necrotic granulomas—typical for single TB infection—are rare in TB/HIV coinfected patients. Despite the same number of granulomas and acid-fast stained bacilli in TB infected and TB/HIV coinfected persons [59], granulomas from dual-infected individuals are easy disrupted and infection can readily disseminate into

**5.1. HIV impact on TB infection**

64 Immunopathology and Immunomodulation

fatal end in coinfected individuals.

HIV recognizes immune cells expressing CD4+ glycoprotein on their surface: CD4+ T-cells, macrophages, and dendritic cells. All of these cellular types are involved in TB pathogenesis and immune response. HIV also needs activated immune cells for replication and propagation; such cells are abundantly present during *M*. *tuberculosis* primary or latent infection. In this way, it can be speculated that TB infection areas (granulomas) create the optimal environment for HIV propagation.

HIV-positive patients who developed TB have an increased viral load during the acute phase of TB disease [65, 66]. Lung tissue samples from patients with TB have increased HIV viral load when compared to HIV-positive patients without lung disease or plasma samples from the same TB patients [67]. This suggests that a TB-infected lung has elevated local HIV replication in vivo. In addition, HIV replication is activated in TB-infected alveolar macro‐ phages [68], lymphocytes, and CD14+ macrophages of the pleural space [69].

Infection with *M*. *tuberculosis* also enhances the level of inflammatory cytokines and chemo‐ kines. Their release stimulates HIV replication and increases viral load. Pleural fluids from patients with active TB provoke HIV replication in vitro via production of TNF-alpha, IL-6, and IFN-gamma [70].

Coinfected individuals have increased incidence and death rate of HIV-related opportunistic infections comparing to HIV-positive but TB-negative patients with the same level of immu‐ nosuppression (absolute CD4+ count) [71], indicating that *M. tuberculosis* accelerates the clinical course and outcome of HIV infection.

#### **6. Concluding remarks**

TB/HIV coinfection represents a leading threat to public health worldwide. Despite the extreme research effort, many aspects of the exceptionally complicated immunology of concurrent TB and HIV infections still need to be elucidated. Diagnosis of HIV/TB coinfection is challenging as both infections have overlapping clinical manifestations, which often lead to late or misdiagnosis. Furthermore, TB and HIV as well the coinfection mostly affect poor and developing regions where competent health care is hardly accessible.

Changes in both innate and adaptive immune response demand well-organized clinical and laboratory studies to understand possible mechanisms by which HIV and TB disrupt in perfect and fatal cooperation the immune system of the host.

#### **Abbreviatons**


TLRs – Toll-like receptors

