Tuberculosis and HIV Co-infection

Deadly Human Syndemic

While expecting her second baby, Shaina was diagnosed with Tuberculosis (TB) and human Wimmunodeficiency virus (HIV) at an antenatal clinic. Her husband divorced her shortly after. She was ill and all alone, fearing what the future would bring for her unborn child. After letting her voice out, a few support workers got in touch with her to talk through her concerns and encouraged her to stay on TB treatment. Shaina’s life has since turned around. She was cured of TB, her baby was born HIV negative, and she has been taking antiretrovirals to stay healthy. A role model in her village today, Shaina wants to give something back and is encouraging people in
her position to not give up on life.

The Global Burden

TB is known since the dawn of recorded history and during the 1 9th century, it was one of the leading causes of morbidity and mortality worldwide. It has long been k n o w n as defin Ingillnessofacquire dimmunodeficiency syndrome (AIDS) in HIV patients, causing corresponding advantages for both the pathogens throughout the disease course. HIV and TB often occur together with each exacerbating the other, and therefore they are a recalled ” Syndemic”. A syndemic is defined as the convergence of two or more diseases that act synergistically to not just constitute a burden for the patient, but also magnify the impacts on public health globally. The intersection and syndemic interaction between HIV and TB epidemics have had deadly consequences around the world. Hence, without sufficient control of this syndemic, the long-term T B elimination target set for 2 050 will be arduous to reach

Chronic Immune Activation

Immune responses ascended against Mycobacterium tuberculosis (MTB) are varied and multifaceted compelling all arms of the host immune system. Many different immune cell subsets have been associated with protection. People with HIV are at a greater risk of developing active TB, which increases with the degree of HIV-induced immunosuppression. The HIV infection hallmark is a significant reduction in CD4+ T cells. But unusual chronic immune inflammation induced by HIV, also damages immune responses, altering the functionality of the remaining CD4+ T cells and impairing subsets of the innate cells. This leads to a complete immune dysfunction favoring the progression of TB disease. This culminates the importance of early antiretroviral treatment for HIV- infected persons to protect against immune system damage and therefore reduce TB-related morbidity and mortality.

Tuberculosis infection is initiated when MTB droplets from other individuals are inhaled, recognized by Pattern Recognition Receptors ( PRRs), and phagocytosed by the alveolar macrophages in the respiratory tract. Post-infection cells mature and recruit a number of processes to eliminate MTB like autophagy, and apoptosis and recruit some innate cells to the site of infection through the secretion of pro- inflammatory cytokines. During this process, pre- granulomas are formed. Infection of dendritic cells with MTB induces maturation and migration to the lymph nodes, where the adaptive immune responses are initiated by priming naive CD4 or CD8 T lymphocytes.

MTB-specific CD4+ T cell responses include a wide array of T helper (Th) subsets endowed with distinct effectors or regulatory functions. These activated T cells migrate back via blood to the lungs and participate in the formation of granulomas.2

Solid granulomas constitute various immune cells, primarily MTB-infected macrophages, and some highly differentiated cells like the multinucleated giant cells, epithelioid cells, and foamy cells, surrounded by a rim of lymphocytes. It is likely that the clinical outcome of MTB infection relies on the capacity of the immune system to bring a balanced response between the effector and regulatory subsets where –

4Pro-inflammatory responses– enhance bacterial killing required to control MTB

4Anti-inflammatory responses– limit pathology and inflammation during initial infection and latency

HIV-induced immune dysregulation can disorganize the granuloma structure. HIV-induced disruption of the resident CD4+ T cells results in a direct disruption of granuloma structure; and combined with alterations of T cell and macrophage function observed during HIV infection, this impairs the capacity of granulomas to contain MTB, enhancing susceptibility to active disease and promoting MTB dissemination.

TB reactivation due to HIV

Almost 10% of MTB-infected individuals develop clinical disease and almost half of them develop the disease two years post-infection; these are called the “reactivation” cases or “post-primary TB”. The risk of developing active TB in immunocompetent adults during their lifetime is around 5%–10%, but in HIV- positive patients, this risk is increased by about 5%–15%.

The depletion of CD4+ T cells is certainly an important contributor to the reactivation of latent TB and increased susceptibility to new MTB infection. There is also some evidence that CD8+ T cells play a role in controlling latent TB. Other mechanisms reported to facilitate MTB infection and disease in individuals with HIV are

4Up- regulation of MTB entry receptors  on macrophages

 

Overview of Immune Response to Mycobacterium tuberculosis Infection and Impact of HIV

4HIV manipulation of macrophage bactericidal pathways

4Deregulated chemotaxis

4Tipped Th1/Th2 balance

HIV also impairs tumor necrosis factor (TNF)-mediated macrophage apoptotic response to MTB and thus helps in bacterial survival.

Despite a seemingly robust Th1 immune response, the bacteria are not completely eradicated in the latent phase of TB. An alteration of the quality in the levels of protective adaptive immune responses or of the cross-talk with innate immune responses leads the way to reactivation of infection. Several immune mechanisms play a role in such reactivation such as

4Increased levels of FoxP3+ Treg cells

4Increased production of IL-27, TGF-β, PGE-2, SOCS1

4The decoy receptor D6

4Extinct levels of IFN-γ, TNF, and polyfunctional specific T cells

Granulomas are the pathologic hallmark of TB, they are organized cellular structures. The Mycobacteria is usually contained within the granulomas, thereby localizing infection and potentially preventing the spread of the disease between hosts, probably contributing to protection. CD4+T cells and TNF organize these granulomas. In patients with compromised immune systems, the formation of granulomas may fail. There are several pathways in which HIV exacerbates TB pathology by manipulating granulomas. TB patients with AIDS present necrosis and dominant granulocytic infiltrate, and there is no typical caseous necrosis seen in non-HIV-infected TB granulomas. This is associated with the CD4+ cell death in the granuloma, resulting in the direct disruption of granuloma structure and abolition of infection containment. Cavitary lesions are often seen in patients with a high CD4 T-lymphocyte count. Therefore, in the majority of TB patients, the infection is confined within

the lungs, whereas in HIV-infected patients TB can be a systemic disease involving multiple organs that lack well-defined granulomas and more diffuse lesions. All forms of extrapulmonary TB have been observed in patients with HIV.

Exacerbation of HIV Infection by MTB Infection

The incidence and mortality rates for new AIDS-defining opportunistic infections have been shown to be higher if individuals with HIV are co-infected with TB. The function of many immune cells, including macrophages and dendritic cells, is modulated by both HIV and MTB. Increased replication of the virus is observed at sites of MTB infection in the lungs and within activated cells, including lymphocytes and CD14+ macrophages, of the pleural space of co-infected patients. MTB can up-regulate HIV replication in chronically or acutely infected T cells or macrophages, as well as in alveolar macrophages and lymphocytes in patients with HIV.

MTB can up-regulate both HIV infection and replication within monocyte-derived macrophages (MDMs), increase the virus transmission from infected MDMs to T cells, and favor replication of HIV variants. While TNF production is necessary for the control of bacterial growth, it is known to activate HIV replication in macrophages, indicating that the host immune response initiated against one pathogen may promote the replication of another. Thus, both HIV and MTB can stimulate TNF release from infected cells and hamper bacterial growth while enhancing HIV

Double stigma

People like Shaina are often most judged and stigmatized. However, health activists have galvanized HIV stigma into a force for social change. HIV-related

discrimination has been confronted with empowerment, HIV testing, treatment, medication access, counselling, and employment of persons with HIV. This has affirmed and upheld the rights of those affected by HIV. But the TB community has done far less to confront the stigma. The risk and fear of transmission for this airborne infection are often raised in defence of practices that prioritize the well-being of the collective public over individual patients. Awareness-raising is insufficient to tackle the structural drivers of stigma. Addressing stigma can strengthen the delivery of equitable, quality healthcare while attending to important disease nuances. Apart from addressing stigma, there is also a desperate need for additional resources and novel approaches for the prevention, diagnosis, and treatment of both HIV and TB. Multidisciplinary approaches that consider HIV and TB in conjugation, rather than as separate diseases, will be necessary to prevent further worsening of the HIV-TB syndemic.3

 

 

 

 

 

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