Introduction Increasing HIV replication with co-infection of
Does infection with Mycobacterium tuberculosis increase
HIV replication?
According to the World Health Organization, 5.6 million people worldwide are co-
infected with HIV and Tuberculosis. This observation has lead to interest in the
correlation between HIV positive infected individuals and potential for increased
susceptibility to tuberculosis infection or reactivation of dormant tuberculosis into its
active state. Infection with Mycobacterium tuberculosis does not always transform
into disease. One fate of this microbe after inhalation is endocytosis by macrophages
and dendritic cells in the lungs which is then contained within a granuloma that is
formed by a layer of CD4+ and CD8+ T cells. The 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. This fact and 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.
http://www.doctorswithoutborders.org/publications/topten/2008/story.cfm?id=3241
Methods
In vivo -
•Plasma sampled from HIV positive individuals in a retrospective cohort study as
well as a prospective cohort study from Baltimore, Italy, and New York before
MTB infections and after successful or unsuccessful MTB treatment
•Matched individuals controlled for CD4+ count and risk factors.
In vitro –
•Examine HIV-1 infected peripheral blood mononuclear cells (PBMC) which
include CD4+, CD8+ lymphocytes, macrophages, and monocytes
•unfractionated PBMCs and CD8+ T cell depleted PBMCs studied to focus on CD4+
T cells, the site of infection of the HIV virus.
Results
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,
HIV-RNA 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.
Mycobacterium tuberculosis
and the Role of the Immune Response
Emily Scroggs, Biology 113, Dr. Tracy Ruscetti, Santa Clara University
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. CD8+ T cells have been seen to decrease HIV viral load and thus, it was depleted from culture to focus
on the interaction between CD4+ T cell count and HIV replication in response to Mycobacterium tuberculosis.
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
Figure 2. Introduction of MTB and PPD into CD8+ T Figure 3. Introduction of MTB and PPD into CD8+ T cell
Conclusions
cell depleted PBMCs from HIV positive, PPD depleted lymph node mononuclear cells induces HIV
• Infection with Mycobacterium tuberculosis increases HIV replication as
positive induces HIV replication. No effect was seen
in the viral load of HIV in unfractionated PBMCs
replication in HIV positive PPD positive cells. The rate
of replication is expected to be higher in lymph nodes seen in the increased amount of HIV RNA numbers during tuberculosis
taken from HIV infected individuals with positive PPD due to the role of lymph nodes in immune response infection as compared to HIV RNA before infection and after successful
tests. Once CD8+ T cells are added back into PBMC and due to the fact that the lymph nodes are a major treatment of Mycobacterium tuberculosis
of HIV Positive, PPD positive sample, HIV replication site of HIV replication. Viral load decreases once CD8+ T
is depleted once again. Cells are added back into the culture. •In vitro, using peripheral blood mononuclear cells and lymph node
mononuclear cells, HIV is increased in CD8+ T cell depleted lymphocytes of
Further experimentation was carried out to evaluate the importance of immune response to MTB in HIV HIV infected, PPD positive individuals after stimulation with MTB or PPD
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 •Increase in HIV replication is most likely due to CD4+ T cell activation to
skin, demonstrating the presence of antigens to MTB in the hose and thus, the host immune response to the pathogenic antigens of Mycobacterium tuberculosis
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,
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Figure 4. No affect is seen on the rate of HIV replication in CD8+ T cell-depleted PBMCs Toossi, Z., H. Mayanja-Kizza, C. S. Hirsch, K. L. Edmonds, T. Spahlinger, D. L. Hom, H. Aung, P.
after stimulation by MTB in PPD negative, HIV positive individuals. The addition of Mugyenyi, J. Ellner, and C. W. Whalen. "Impact of Tuberculosis (TB) on HIV-1 Activity in Dually
PHA+IL-2+IL-4 is used as a positive control and KLH is the negative control in this Infected Patients." Clinical and Experimental Immunology 123 (2001): 233-38. Web.
experiment. This data suggests a role of the immune response to MTB as essential to
increase in HIV replication.