Researchers know well the terrible progression from HIV infection to AIDS, but they're less clued in to how the virus gets a toehold in the body. The virus--which attacks immune cells called CD4 T lymphocytes--shows up early on in the lymph nodes. But a study in today's Science  suggests the virus may strike first with a sucker punch to CD4 T cells in the gut, holing up there while it replicates. The finding could help scientists develop drugs and vaccines to disarm HIV before it spreads.
Usually CD4 T cells act as sentries that roam the body's lymph and blood in a dormant state until they encounter a foreign antigen, which triggers them to attack the invader. Ironically, these "activated" cells are especially vulnerable to HIV, which tricks the activated cells into letting it enter. Then it slips its genetic material into the cell's DNA so it can propagate and eventually kill the cell. Because many lymphocytes congregate in the intestine, previous work had looked there for early signs of HIV infection. But gut tissue samples were hard to obtain, and it was difficult to tell how long the person had been infected.
To get a clearer picture, researchers at the Harvard Medical School Primate Center in Southborough, Massachusetts, worked with SIV--the simian analog of HIV. The researchers inoculated a group of macaque monkeys with SIV, then killed two at weekly intervals to study the levels of CD4 T cells in the gut. Even though CD4 T levels didn't drop in the monkeys' blood for nearly 2 months, the researchers found that the population of CD4 T cells in the intestine was almost halved during the first week. And by the third week, only a small percentage of cells remained. "It was pretty surprising," says Andrew Lackner, head of comparative pathology at the primate center. "We spent a long time convincing ourselves there wasn't another explanation."
"It's a quite important paper," says Marion Neutra, a mucosal biologist at Children's Hospital in Boston. The intestine has been largely overlooked as a launching point for HIV, she says, but it makes sense the virus would start there. "Many of the T cells in the gut are activated" because of their exposure to foreign bodies, she says, making them "prime targets for infection." The idea "seems very plausible," adds William Paul, chief of immunology at the National Institute of Allergy and Infectious Diseases, in Bethesda, Maryland. One implication is that any HIV vaccine would have to build immunity in the gut, Paul says.