Flushing Out the AIDS Virus

New combination drug therapies might be able to drive the AIDS virus from at least one of its hideouts in the body. Researchers report in the 9 May issue of Science* that a three-drug cocktail can dramatically reduce the amount of HIV RNA lurking in the lymph nodes, a major reservoir of the virus.

Potent combinations of drugs that attack two critical viral enzymes, reverse transcriptase (RT) and protease, have already shown that they can lower the amount of HIV RNA in a person's blood to levels too low for the most sensitive assays to detect. The new results raise hopes of doing the same thing in the lymph nodes, which had looked unassailable. But HIV is still impervious to attack when it goes underground, transforming its genetic material from RNA into DNA and concealing itself among the host cell's own genes.

The University of Minnesota's Ashley Haase, Winston Cavert, and their co-workers repeatedly biopsied the tonsils (a type of lymph node) of 10 patients who were receiving the RT inhibitors AZT and 3TC plus the protease inhibitor ritonavir. Over a period of 6 months, the researchers found, the drugs rapidly decreased the levels of HIV RNA inside certain kinds of immune cells called mononuclear cells. The drop was not surprising, because mononuclear cells travel between the lymph nodes and the blood, where the virus already has been shown to be vulnerable to drugs. More startling was the finding that HIV RNA trapped on the surface of immune cells that form the scaffolding of lymph nodes--follicular dendritic cells (FDCs)--dropped off at roughly the same rate. Based on earlier test-tube studies, says Haase, "we were thinking it would take months, if not years, to clear this virus."

It's "quite a novel finding," says John Coffin, a retrovirologist at Tufts University in Medford, Massachusetts. But Haase cautions that even though the drugs have rid patients' lymph nodes of HIV RNA within a few months, nobody's been cured. "There's clearly a residue of virus still stored on FDCs, and if you stop therapy, there's every indication that you can restart the infection," says Haase.

The cells harboring HIV DNA are still more intractable. No one knows how long they survive, how many such cells exist in an infected person, and how much new virus they can produce. Robert Siliciano of Johns Hopkins University and colleagues addressed these issues by studying HIV DNA levels in nondividing white blood cells of the type known as CD4 from the blood and lymph nodes of 14 patients, half of whom were receiving treatment. As they report in tomorrow's issue of Nature, fewer than 0.05% of the cells harbored viral DNA, but many of them, when stimulated to divide, were capable of producing virus. "These cells can survive for months or years," says Siliciano. "They represent the potential barrier for curing the infection."

* Science Online subscribers can link to the full text of the Report after 5 p.m. EST, Thursday, 8 May.

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