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Scientists seeking HIV in all the wrong places
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Nature Medicine November 2004, Vol 10, No 11
Helen Pearson
New York
HIV's abundance in the gut may mean vaccines should be refocused. Bumps of lymphoid tissue seen in a normal gut are wiped out by HIV.
HIV annihilates immune cells in the gut rather than the blood, a surprising discovery that, experts say, may require a total rethink of strategies to design HIV drugs and vaccines.
HIV infects and destroys a subset of disease-fighting cells called CD4+ T cells. Doctors routinely measure levels of these cells in the blood to monitor virus progression and to evaluate the effectiveness of experimental drugs and vaccines. Based on these measurements, it is widely assumed that HIV does not wipe out large quantities of these cells until months or years into the infection.
Two papers published in September shatter that assumption by showing that the virus demolishes T cells in the gut within weeks of infection (J. Exp. Med. 200, 749--759; 2004 and J. Exp. Med. 200, 761--770; 2004). "It's an enormously important observation," says microbiologist Ronald Desrosiers, who studies monkey models of HIV at Harvard Medical School.
"It may be we've been barking up the wrong tree"
Ronald Desrosiers
Harvard Medical School The discovery suggests that measuring T cells in the blood will not accurately portray the damage being wreaked by the virus elsewhere in the body, or whether therapies are taking effect. Indeed, one of the two teams showed that the T-cell population in the gut does not recover in chronically infected patients taking antiretroviral therapy, even if their blood counts improve. Because gut biopsies are so invasive, however, they are unlikely to become a normal part of disease monitoring.
Desrosiers says the finding should also refocus efforts to find a vaccine. At present, vaccines are designed to boost T-cell levels in the blood. But a vaccine that specifically protects the gut from infection, perhaps by being swallowed rather than injected, might be more effective. "It may be we've been barking up the wrong tree," says Desrosiers. He and others have already begun working on experimental forms of such vaccines.
The idea that HIV might attack T cells in the gut stemmed from a 1998 study showing that HIV's simian counterpart, SIV, does the same in the gastrointestinal tract of monkeys (Science 280, 427--431; 1998). But it was difficult to repeat the work in newly infected patients reluctant to undergo uncomfortable gut biopsies.
Part of the explanation for the damage in the gut may be that a large proportion of T cells there display CCR5, a receptor that HIV uses to infect cells. The gut also harbors the vast majority of the body's T cells to fight off pathogens in food; the blood, by contrast, carries only 2--5%. "That explains why the depletion is so dramatic," says Danny Douek, a researcher at the US National Institute of Allergy and Infectious Diseases, who led one of the studies.
Besides its implications for vaccines, the studies back the case for developing drugs that specifically protect the gut. They also argue for using antiretroviral therapy in high-risk individuals as a preventative treatment to block the virus from establishing infection early on. "Personally, I feel this should be pursued with extreme vigor," says Desrosiers.
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