Introduction:

Does infection with Mycobacterium tuberculosis increase HIV replication?

According to the World Health Organization, 5.6 million people worldwide are coinfected with HIV and Tuberculosis. This observation has lead to interest in the interaction between these two diseases and has inspired research that has shown a correlation between HIV positive infected individuals and increased susceptibility to tuberculosis infection or reactivation of dormant tuberculosis into its active state. Infection with Mycobacterium tuberculosis does not always transform into disease due to the fact that one fate of this microbe once inhaled is for it to be taken up by macrophages and dendritic cells once in the lungs. The microbe is then contained within a granuloma that is formed by a layer of CD4+ and CD8+ T cells that form due to antigens that present after inhaling tuberculosis droplets. This granuloma allows the tuberculosis to remain in a latent stage in the host for as long as the host retains a healthy immune system. However, many factors can force this microbe out of dormancy including co-infection with HIV which resides in CD4+ T cells and leads to T cell death and immunodeficiency. Further epidemiological observations of the increasing rates of co-infection of HIV with tuberculosis have suggested that HIV replication is increased in the presence of active tuberculosis. The purpose of this paper is to evaluate the effects of active tuberculosis on HIV replication and thus, on the virulence of the human immunodeficiency virus and to examine the mechanisms by which HIV and Mycobacterium tuberculosis interact.

Effect of Mycobacterium tuberculosis on HIV Replication and the Role of Immune Response
MTB induces HIV replication in peripheral blood mononuclear cells and in lymph node mononuclear cells. The depletion of the CD8+ T cells allows for the examination of the CD4+ T cell activity independent of CD8+ T cell activity. It is possible that the CD8+ T cells play a role in destroying infected CD4+ T cells and thus would diminish the effects of MTB on HIV replication.

Figure 5. Cell proliferation, activation, and cell death of CD4+ T cells are associated with PPD- and MTB- HIV replication in CD8+ T cell depleted PBMC. A, Cell proliferation is seen in HIV infected PBMCs with addition of MTB or PPD as measured by the incorporation of labeled H-thymidine. B, Cell activation is induced in HIV infected PBMCs with addition of MTB or PPD as measured by expression of CD25 in CD4+ cells. C, IL-2 secretion is another indicator of CD4+T cell activation and is also increased in HIV positive, PPD positive PMBCS after introduction of MTB or PPD. D, The antigen dependent pathway of cellular activation of CD4+ T cells induced cell death of T cells after prolonged exposure to MTB or PPD

Conclusions
http://www.doctorswithoutborders.org /publications/topten/2008/story.cfm?id=3241

Methods This study measured the in vivo and in vitro effects of MTB on HIV replication. Plasma was sampled from individuals from a retrospective cohort study as well as a prospective cohort study from Baltimore, Italy, and New York. The samples were taken from individuals that were HIV positive before MTB infection as well as from these individuals after successful or unsuccessful treatment of MTB. Matched controls were used for each patient that controlled for CD4+ count and risk factors. The in vitro study used peripheral blood mononuclear cells (PBMC) which include CD4+, CD8+ lymphocytes, macrophages, and monocytes that were infected with HIV-1. In addition, mechanisms of MTB on the replication of HIV were evaluated by examining both unfractionated PBMCs and CD8+ T cell depleted PBMCs in order to focus the study on CD4+ T cells. CD 4+T cells are the site of infection of the HIV virus.

Figure 2. Introduction of MTB and PPD into CD8+ T cell depleted PBMCs from HIV positive, PPD positive induces HIV replication. No effect was seen in the viral load of HIV in unfractionated PBMCs taken from HIV infected individuals with positive PPD tests. Once CD8+ T cells are added back into PBMC of HIV Positive, PPD positive sample, HIV replication is depleted once again.

Figure 3. Introduction of MTB and PPD into CD8+ T cell depleted lymph node mononuclear cells induces HIV replication in HIV positive PPD positive cells. The rate of replication is expected to be higher in lymph nodes due to the role of lymph nodes in immune response and due to the fact that the lymph nodes are a major site of HIV replication. Viral load decreases once CD8+ T Cells are added back into the culture.

Infection with tuberculosis increases HIV replication as seen in the increased amount of HIV RNA numbers during tuberculosis infection as compared to HIV RNA before infection and after successful treatment of Mycobacterium tuberculosis In vitro, using peripheral blood mononuclear cells and lymph node mononuclear cells, HIV is increased in CD8+ T cell depleted lymphocytes of HIV infected, PPD positive individuals after stimulation with MTB or PPD Increase in HIV replication is most likely due to CD4+ T cell activation to pathogenic antigens of Mycobacterium tuberculosis

Results

Further experimentation was carried out to evaluate the importance of immune response to MTB in HIV infected individuals. This is measured by PPD positivity. PPD is a derivative of Mycobacterium tuberculosis that when injected in a small amount to the skin of an individual infected with MTB, creates a raised area in the skin, demonstrating an immune response to the MTB. This is a primary test of tuberculosis infection.

Activation of CD4+ T cells infected with HIV end in cell death and depletion of T cells CD8+ T cells can inhibit viral replication of CD4+ T cells

References
Goletti, Delia, Drew Weissman, Robert W. Jackson, Neil M. Graham, David Vlahov, Robert S. Klein, Sonal S. Munsiff, Luigi Ortona, Robert Cauda, and Anthony S. Fauci. "Effect Mycobacterium Tuberculosis on HIV Replication: Role of Immune Replication." The Journal of Immunology 157 (1996): 1271-278. Web. Kaufmann, Stefan H., and Andrew J. McMicheal. "Nature Medicine." Annulling a Dangerous Liaison: Vaccination Strategies against AIDS and Tuberculosis 11.4 (2005): 33-44. Web. Toossi, Z., H. Mayanja-Kizza, C. S. Hirsch, K. L. Edmonds, T. Spahlinger, D. L. Hom, H. Aung, P. Mugyenyi, J. Ellner, and C. W. Whalen. "Impact of Tuberculosis (TB) on HIV-1 Activity in Dually Infected Patients." Clinical and Experimental Immunology 123 (2001): 233-38. Web.

Figure 1. HIV RNA copy number increases during active stage of MTB infection as compared to number of copies before infection and after successful therapy. A, HIVRNA levels increased during MTB infection by up to 160 fold as compared to viral load before infection and after successful therapy of MTB. B, There is no decrease in viral load of HIV after infection with MTB if treatment of MTB is unsuccessful or if the patient was noncompliant with the treatment. C, Data from matched controls to each patient. Controls were matched for risk factors and CD4+ T cell counts.

Figure 4. No affect is seen on the rate of HIV replication in CD8+ T cell-depleted PBMCs after stimulation by MTB in PPD negative, HIV positive individuals. The addition of PHA+IL-2+IL-4 is used as a positive control and KLH is the negative control in this experiment. This data suggests a role of the immune response to MTB as essential to increase in HIV replication.

Poster by: Emily Scroggs