One of the many questions surrounding AIDS has been where HIV comes from in the latter stages of the disease, when the patients have low CD4 T cell counts. A report in the June 20 issue of Science identifies a source as tissue macrophages, and points to opportunistic infections as a trigger that sets off a wave of HIV production.
This finding has several important implications, according to investigators Dr. Jan Orenstein from George Washington University and Dr. Sharon Wahl from the National Institute of Dental Research. "Preventing or eliminating opportunistic infections is not only essential to the immediate well-being of the patient, but can also slow the cycle of virus production that leads to further immune system damage," said Dr. Wahl. "The macrophage appears to be a key player in this scenario by functioning as a long-lived reservoir of virus production. " It has been known for some time that CD4 T cells are the primary target of HIV infection, and that their destruction leads to a weakened immune system and susceptibility to "opportunists"--microorganisms that normally don't infect a healthy individual. As HIV infection progresses toward AIDS, the CD4 T cells are the chief source of new virus, creating a cycle of escalating virus production and T cell death. The paradox has been how the levels of HIV continue to increase over the course of AIDS, at the same time the T cell population dramatically decreases.
Drs. Orenstein and Wahl thought macrophages might hold the answer to this riddle. Macrophages are immune cells that roam throughout the tissues for periods from months to perhaps years, seeking out and destroying invading organisms. The scientists knew that macrophages could be infected with HIV, but these voracious scavengers were not thought to be a significant source of virus production.
Close examination of lymph nodes from AIDS patients infected with a variety of common opportunists, including Pneumocystis carinii and Mycobacterium avium, proved otherwise. These patients not only had from 5 to over 100 times the number of virus-producing macrophages found in the nodes of opportunist-free HIV patients, the individual macrophages also demonstrated a much higher level of virus production.
The actual mechanism that switches macrophages from HIV carriers to producers is not yet known. Opportunistic microorganisms apparently act as a magnet, say the investigators, pulling together large numbers of both HIV-infected and uninfected macrophages. The opportunists then in some way stimulate the HIV-infected macrophages to produce virus, which ultimately spreads to uninfected macrophages and T cells.
The members of the research team were Dr. Jan Orenstein, George Washington University, Washington, DC; Dr. Cecil Fox, Molecular Histology, Inc., Gaithersburg, MD; and Dr. Sharon Wahl, National Institute of Dental Research, National Institutes of Health, Bethesda, MD
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Journal
Science