In HIV-infected people who develop active tuberculosis (TB), levels of HIV in the bloodstream increase five- to 160-fold, according to investigators at the National Institute of Allergy and Infectious Diseases (NIAID). The new findings, which build on previous work at NIAID and elsewhere, help explain why HIV-infected people with active TB have a poorer prognosis than HIV-infected people without TB.
Delia Goletti, M.D., Ph.D., of the NIAID Laboratory of Immunoregulation (LIR) and her colleagues report their findings in the Aug. 1 Journal of Immunology.
Recent research has demonstrated that high levels of HIV in the blood correlate with an increased risk that an HIV-infected person will develop AIDS or die," says LIR Chief and NIAID Director Anthony S. Fauci, M.D. "Our new findings that active TB disease boosts HIV levels in the blood underscore the importance of diagnosing and effectively treating tuberculosis in HIV-infected people."
In addition, adds Dr. Goletti, "These results highlight the importance of preventive TB therapy in HIV-infected people. Such therapy may not only help to control the spread of TB, but also prevent the increased replication of HIV associated with active TB."
The World Health Organization estimates that 5.6 million people worldwide and 80,000 people in the United States are co-infected with HIV and Mycobacterium tuberculosis (M.tb.), the organism that causes TB.
Previously, the NIAID researchers and others have shown in the test tube and in HIV-infected people that immune system activation by stimuli such as opportunistic infections and immunizations boosts the replication of HIV.
The normal efforts of the immune system to mobilize itself and fight an invader may also result in the increased production of HIV," explains Dr. Fauci. "Chronic immune activation, or the cumulative effect of multiple episodes of immune activation and bursts of virus production, probably contribute to the progression of HIV disease," says Dr. Fauci.
In the current study, the researchers collected blood samples from seven patients with HIV infection and active TB, as well as from seven HIV-infected patients who did not have TB disease but were otherwise similar to the first group of patients.
In patients with TB, the investigators found that the number of HIV RNA copies per cubic millimeter of plasma increased up to 160-fold during the acute stage of TB, compared with levels before the onset of disease and after successful treatment. In two patients for whom anti-TB treatment was not successful -- one patient did not adhere to the TB treatment regimen and one had a drug-resistant strain of TB -- HIV RNA levels did not decrease following treatment. In the control group of HIV-infected patients (without TB), HIV RNA levels did not change significantly.
In further experiments with two different cell culture systems, the researchers demonstrated that both M.tb. and purified protein derivative (PPD) from the TB organism boosted HIV replication in immune system cells taken from people who tested positive to the PPD test, but not in cells from patients who were PPD-negative. In each system, induction of viral replication correlated with CD4+ T cell activation. The researchers speculate that enhancement of HIV replication likely was due to activation of the specific cells that respond to TB antigens previously "seen" by the immune system.
Co-authors of Dr. Goletti and Dr. Fauci include: Drew Weissman, M.D., Ph.D., and Robert W. Jackson of LIR; Neil M.H. Graham, M.D., and David Vlahov, Ph.D., of The Johns Hopkins University; Robert S. Klein, M.D., and Sonal S. Munsiff, M.D., of the Albert Einstein College of Medicine; and Luigi Ortona, M.D., and Roberto Cauda, M.D., of the Catholic University in Rome, Italy.
NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as AIDS and other sexually transmitted diseases, tuberculosis, asthma and allergies. NIH is an agency of the U.S. Public Health Service, U.S. Department of Health and Human Services.
Goletti D, et al. Effect of Mycobacterium tuberculosis on HIV replication: role of immune activation. Journal of Immunology 1996;157:1271-1278 (Aug. 1, 1996).