(AIDSmeds.com)—It is well known that HIV-positive people often experience healthy increases in their CD4 (T4 cell) counts after starting antiretroviral therapy. Unfortunately, two new studies reported in online versions of PLoS Medicine and the Journal of Virology suggest that CD4 counts in other parts of the body—notably the mucosal tissues of the gut—are much less likely to rebound in response to treatment.
A handful of studies reported to date (including a University of California study reviewed by AIDSmeds.com in July) have demonstrated that within two to four weeks after HIV infection is established in he body, the mucous membrane of a patient's gastrointestinal (GI) tract – tissue that is usually rich in disease-fighting white blood cells – can lose up to 60% of its CD4 cells.
Taking these results one step further, Saurabh Mehandru, MD, of New York's Aaron Diamond AIDS Research Center (ADARC) and his colleagues set out to determine whether this mucosal loss of CD4 cells was reversible with the use of antiretroviral therapy.
The study conducted by Dr. Mehandru's group enrolled 40 HIV-positive people who began antiretroviral therapy shortly after contracting the virus – during the acute/early infection phase – and followed them from one to seven years. While the researchers found that the blood population of CD4 cells rebounded to normal levels in the vast majority of patients, a subset of the GI tract CD4 cell population remained depleted in 70% of the patients.
"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," says ADARC's Martin Markowitz, MD. "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, he explained, most patients still had only half the normal number of CD4 effector memory T cells – responsible for recognizing disease-causing microorganisms and priming other immune system cells for attack – in their GI tracts.
"Obviously the first question is, 'why, what's the mechanism?' " Dr. Markowitz says.
A second paper, published online in the Journal of Virology, makes some headway toward an answer. By examining the amount of HIV-DNA and HIV-RNA in cells from the GI tract, and comparing that to cells from the blood, Drs. Mehandru's and Markowitz's team determined that the mucosal lining of the GI tract carried a disproportionately high viral load. This likely explains the initial loss of CD4 cells in that area. 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 CD4 cells self-destruct – a process called apoptosis – while some appear to be killed by other immune system cells.
"These papers speak strongly to HIV pathogenesis, to HIV therapy, and to understanding how the host and virus interact," Dr. Markowitz says. However, he adds, the short and long term consequences of the persistence of this depletion remain unknown.
The finding that immune cells of the intestinal mucosa remain depleted and over-activated for years, despite antiretroviral treatment, raises the concern that health problems may arise down the line. For example, Dr. Markowitz suggests that it could potentially lead to an increased risk of polyps or colorectal cancer. This may call for HIV-positive patients receiving colonoscopies earlier and perhaps more frequently than current recommendations suggest.
The new data also pose a challenge to HIV vaccine developers. "What good is a vaccine going to be if you get immune responses in peripheral blood but there's nothing in tissue?" Dr. 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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