December 5, 2006

HIV's Effect on the Immune System Worse than Thought

People with HIV have been living longer and better since the development of highly active antiretroviral therapy (or HAART) in 1995. In fact, most do so well on HAART that immune cells in the blood sometimes bounce all the way back to pre-HIV levels.

Two new studies, however, have found that immune cells in other parts of the body may never recover, suggesting the need for better ways to assess immune system health, as well as the need to monitor the HIV-positive especially carefully as they live into their forties, fifties, sixties and beyond.

Earlier research had shown that, just two to four weeks after contracting HIV-1, the gastrointestinal (GI) tract can lose up to 60 percent of its CD4 memory T cells — immune cells responsible for recognizing invaders and priming other cells for attack. Intrigued, Martin Markowitz, Aaron Diamond Professor at Rockefeller University, wanted to know whether this loss was reversible, and whether giving patients HAART during the early infection period helped restore these cells to the GI lining the way it restored them to the blood itself.

In a paper published in the December, 2006 issue of PLoS Medicine, Markowitz, Rockefeller University researcher Saurabh Mehandru and colleagues report on a trial of 40 HIV-1 positive patients who began treatment with HAART shortly after contracting the virus. Over the ensuing one to seven years, the researchers found that although the blood population of CD4 T cells rebounded to normal levels, some of the CD4 T cells in the GI tract remained depleted in 70 percent of subjects.

"If we sample the blood, it only has two percent of the total volume of these cells. It doesn't give us the whole picture," Markowitz says. "But if we actually go into tissue, we see something different. What we see there is eye-opening."

After three years of intensive drug therapy that suppresses HIV replication very effectively, most patients still had only half the normal number of CD4+ effector memory T cells in their GI tracts.

"Obviously the first question is, why? What's the mechanism?" Markowitz says.

A second paper, published online in the December 2006 Journal of Virology, attempts to provide an answer. By examining the viral burden of DNA and RNA in cells from the GI tract, and comparing that to cells from the peripheral blood, Markowitz, Mehandru and their collaborators determined that the mucosal lining of the GI tract carried a disproportionately heavy viral load. That means that the initial loss of CD4 T cells in that area is partially due to virus activity. But the researchers also found evidence suggesting that there are at least two more ways in which the cells were being killed off. Some of the T cells self-destruct (a process called apoptosis), while some appear to be killed by other immune cells.

In the clinic, if the loss of CD4 T cells in the GI tract translates into increased incidence of colonic polyps or colorectal cancer, routine monitoring practices will have to be re-examined, with HIV-positive patients receiving colonoscopies earlier and perhaps more frequently than current recommendations allow.

"What good is a vaccine going to be if you get immune responses in peripheral blood but there's nothing in tissue?" Markowitz says. "It's pretty clear that a successful vaccine will need to address issues surrounding mucosal immunity, which is an area that — relatively speaking — has been previously ignored."
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