People with HIV have been living longer, healthier lives since the development of highly active antiretroviral therapy (or HAART) in 1995. In fact, most patients on the drug regimen do so well that, according to blood tests, their immune cells appear to return to pre-HIV levels. But two new studies from Rockefeller University and the Aaron Diamond AIDS Research Center (ADARC) show that the immune cells in other body tissues may never rebound, suggesting the need for additional ways to monitor immune system health, and the need for hypervigilance as HIV-positive patients live into their forties, fifties, sixties and beyond. The findings are reported in today's issue of PLoS Medicine and online in the Journal of Virology.
Prior research had shown that, just two to four weeks after contracting HIV-1, the lymphoid tissue layer in the mucous membrane of a patient's 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, an Aaron Diamond Professor at Rockefeller University and a staff scientist at ADARC, 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 today in PLoS Medicine, Markowitz, Rockefeller researcher and clinical scholar Saurabh Mehandru, and their colleagues report on a trial of 40 HIV-1 positive patients who began treatment with HAART shortly after contracting the virus -- during the acute early infection phase -- and who they followed from one to seven years. The researchers found that although the blood population of CD4 T cells rebounded to normal levels, a subset of the GI tract population remained depleted in 70 percent of their 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 Journal of Virology, makes some headway toward 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 activation-induced cell death or apoptosis), while some appear to be killed by other cytotoxic immune cells.
"These papers speak strongly to HIV pathogenesis, to HIV therapy, and to understanding how the host and virus interact," Markowitz says. However, the short and long term consequences of the persistence of this depletion remain unknown.
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. In the laboratory, these findings should give researchers another angle with which to approach HIV vaccines.
"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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