While tuberculosis is one of the world’s oldest surviving plagues and HIV-1 infection is one of medicine’s newest challenges, there is an undeniable relationship between HIV/AIDS and tuberculosis. Independently, Mycobacteria tuberculosis and HIV are formidable pathogens but in concert, the prospects for controlling either epidemic are jeopardized. TB-HIV coinfection and interaction complicate all aspects of each disease: pathogenesis, epidemiology, clinical presentation, diagnosis, treatment, prevention, and even social and economic issues.
Not only are individuals more likely to undergo tuberculosis infection if living with HIV, depending on their geographic location, people living with HIV infection are 6-50 times more likely to develop active TB than people living without HIV. Thus, with one-third of the world’s population at least latently infected with Mycobacteria tuberculosis, the current pace of new HIV-1 infections threatens public health on a wide scale.
Tuberculosis infection is believed to have the greatest potential among other common opportunistic infections to increase viral load and to accelerate HIV-1 disease progression. This is in part due to the chronic nature of active TB disease, the marked increase in tumor necrosis factor-alpha (TNF-α) expression for macrophage activation, and intensified antigen presentation causing the recruitment of CD4 T lymphocytes to the site of TB infection.
Manoff and others demonstrated that active tuberculosis is associated with increased viral load in HIV-1 infected patients. Also, TB-HIV coinfected persons have a significantly higher HIV RNA load than persons without opportunistic infections and similar CD4 cell counts.
Figure 1. Schematic hypothetical individual’s of risk of TB infection compared to CD4 cell count.
From: Havlir, Diane V., Haileyesus Getahun, and Ian Sanne. “Opportunities and Challenges for HIV Care in Overlapping HIV and TB Epidemics.” Journal of the American Medical Association 300.4 (2008): 423-430.
Researchers from Case Western Reserve University demonstrated that not only do TB-HIV co-infected patients have significantly higher viral loads than those without TB, the timing of infection by M. tuberculosis affects HIV-1 disease progression. In fact, these researchers showed that TB had its strongest impact on HIV-1 viral load when patients are least immunodeficient. Furthermore, from the same study, more than 25% of TB-HIV coinfected patients developed TB when their CD4 cell counts were at least 500 cells/µl. Thus TB infection is unique because it can occur at any CD4 cell count level.
Perhaps the most problematic tuberculosis-induced effect contributing to HIV-1 disease progression is its apparent impact on HIV-1 evolution. While reverse transcriptase, a polymerase without proofreading capabilities, provides an effective mechanism for genetic diversity, M. tuberculosis infection increases HIV-1 heterogeneity through compartmentalization.
In a cohort of patients matched by their CD4 cell counts, dually infected TB-HIV patients were found to have greater systemic, or more general, HIV-1 heterogeneity and more frequent occurrences of distinct HIV-1 quasispecies than HIV-1 patients without TB infection. A population of diverse quasispecies increases the viral capacity to evolve and adapt to the host immunological response. Furthermore, upon examination of the lung sites of M. tuberculosis infection of TB-HIV coinfected patients, Collins and others found greater genetic HIV-1 heterogeneity and distinct quasispecies in the pleural space compared to blood samples. While phylogenetically distinct HIV-1 subpopulations have been shown to develop in other organs or tracts in humans (i.e. kidneys, brain, urogenital tract and blood), compartmentalization of HIV-1 occurs most significantly and is more defined in the lungs of co-infected TB-HIV patients. Therefore, the lungs, induced by active tuberculosis disease, function as a reservoir for genetically diverse HIV-1.
In addition to accelerating the disease progression of one another, their collision has highlighted underlying public health and human rights failures. Africa, although only home to 10% of the world’s population, is the major site of intersection between the two epidemics with an astounding 75% of the world’s TB-HIV coinfections.
Figure 2. The disproportionate incidence of HIV and HIV-TB coinfection in Africa in 2000. Each person indicates 5% of the global population. The African population is shaded red while blue represents the rest of the world.
From: Corbett, Elizabeth L, Barbara Marston, Gavin J. Churchyard, and Keven M. De Cock. “Tuberculosis in Sub-Saharan Africa: Opportunities, Challenges, and Change in the Era of Antiretroviral Treatment.” Lancet 367 (2006): 926-937.
Thus, novel TB diagnostic tests are needed in HIV-endemic regions because HIV infection reduces the sensitivity of current diagnostic methods such as direct smear sputum microscopy. In terms of treatment, high pill burden and toxicity often discourage adherence among many coinfected patients. Furthermore, rifampicin, a common antibiotic component of tuberculosis chemotherapy disrupts antiretroviral treatment by accelerating the metabolism of both protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTs). Finally, if antiretroviral treatment of coinfected patients is started too soon after treatment for TB, a rapid recovery of CD4 T cell levels may induce an overwhelming inflammatory response against previously hidden opportunistic infections resulting immune reconstitution inflammatory syndrome (IRIS).
The connection between the biology of the two diseases is clear and complications are numerous. Thus, experts in HIV and experts in TB should respond accordingly and move towards greater collaboration and shared research.
Until next, this is Justin Eusebio.
For more information:
Bartlett, John G. “Tuberculosis and HIV Infection: Partners in Human Tragedy.” Journal of Infectious Diseases 196 (2007): S124-5.
Collins, Kalonji R., Miguel E. Quioñones-Mateu, Mianda Wu, Henry Luzze, John L. Johnson, Christina Hirsch, Zahra Toossi, and Eric J. Arts. “Human Immunodeficiency Virus Type 1 (HIV-1) Quasispecies at the Sites of Mycobacterium tuberculosis Infection Contribute to Systemic HIV-1 Heterogeneity.” Journal of Virology 76.4 (2002): 1697-1706.
Collins, Kalonji R., Miguel E. Quioñones-Mateu, Zhara Toossi, and Eric J. Arts. “Impact of Tuberculosis on HIV-1 Replication, Diversity and Disease Progression.” AIDS Review 4 (2002): 165-176.
Kalonji Collins et. al, “Greater diversity of HIV-1 quasispecies in HIV-infected individuals with active tuberculosis.” Journal of Acquired Immune Deficiency Syndrome 24, 408-417.
Friedland, Gerald, Gavin J. Churchyard, and Edward Nardell. “Tuberculosis and HIV Coinfection: Current State of Knowledge and Research Priorities.” Journal of Infectious Diseases 196 (2007): S1-3.
Manoff, SB, H Farzadegan, A Muñoz, JA Astemborski, D Vlahov, RT Rizzo, L Solomon, and NM Graham. “The Effect of Latent Mycobacterium tuberculosis infection on Human Immunodeficiency Virus (HIV) Disease Progression and HIV RNA Load Among Injecting Drug Users.” The Journal of Infectious Diseases 174.2 (1996): 299-308.
Nunn, Paul, Alasdair Reid, Kevin De Cock. “Tuberculosis and HIV Infection: The Global Setting.” The Journal of Infectious Diseases 196 (2007): S5-14.
Vignuzzi, Marco, Jeffrey K. Stone, Jamie J. Arnold, Craig E. Cameron, and Raul Andino. “Quasispecies Diversity Determines Pathogenesis through Cooperative Interactions within a Viral Population.” Nature 439.7074 (2006): 344-348.
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