In HIV Infection, HAART Little Help to Gut Immune Cells

NEW YORK, Dec. 5 -- Even when HIV is well-controlled in the bloodstream, the gut is suffering a fierce assault on immune cells, according to researchers here.

While the attack isn't clinically obvious, it may have long-term effects, especially as people with HIV age, reported Martin Markowitz, M.D., of the Aaron Diamond AIDS Research Center, and colleagues, in the December issue of PLoS Medicine.

Highly active anti-retroviral therapy (HAART) usually results in a complete reconstitution of the immune system in the peripheral blood, but reconstitution is slower -- and in some cases may not occur -- in the mucosal tissue of the gut, Dr. Markowitz said.

The finding emerged from a study of 54 men who were given HAART to treat an early acute infection and 18 uninfected controls. Follow-up, including colonic biopsies, lasted up to seven years.

"If we sample the blood, it only has 2% of the total volume of these cells," Dr. Markowitz said. "It doesn't give us the whole picture."

But looking at the immune tissue in the gut gives a different and "eye-opening" picture, he said. "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."

Earlier research in macaques and in a small number of HIV-infected humans had suggested that early HAART might allow the immune tissue in the gut to recover, in the same way the peripheral blood system does.

Of their volunteers, Dr. Markowitz and colleagues said, 32 underwent colonic biopsies before beginning HAART (but after infection) and again at intervals over a three-year period. Another 22 were followed longitudinally for up to seven years.

The uninfected controls had, on average, a CD4 percentage of 59.6% in peripheral blood mononuclear cells and 56.4% in mucosal mononuclear cells. By contrast, flow cytometry showed that HIV patients in the early acute stage had an average CD4 percentage of 41.5% in the peripheral blood and 19.3% in the mucosal cells.

HAART restored the blood immune system but did not significantly improve the mucosal system, the researchers found.

For instance, in patients treated for one to three years, the average blood CD4 percentage improved to 58.1%, but the mucosal cell percentage remained low at 42.3%. The difference between the mucosa of controls and patients was statistically significant at P=0.003.

The researchers also found that sites in the mucosa where CD4 cells are "trained" (immune inductive sites) were less affected by the depletion than those regions where the cells were in active battle against the virus (effector sites).

Hardest hit among CD4 cells were those expressing either or both of the HIV receptors CCR5 and CXCR4, Dr. Markowitz and colleagues found.

The study, although relatively large, had some important limitations. The study population was not random -- it consisted of patients willing to undergo repeated biopsy. Also, the control group was small and wasn't matched to the HIV-infected volunteers.

Nonetheless, the findings are valuable, said Ronald Veazey, DVM, Ph.D., and Andrew Lackner, DVM, Ph.D., of the Tulane National Primate Research Center in Covington, La.

Writing in an accompanying comment article, they said the findings suggest that "the major battle against HIV occurs in sequestered mucosal tissue sites," which are not reached by current medications.

That observation opens a number of potential therapeutic options, they said, including the development of drugs that will better penetrate the mucosa.

The journal in an editorial note also pointed out that "the results of this study suggest that we should remain vigilant for gastrointestinal problems resulting from impaired immunity over time."

In addition, the note said, "these results suggest that a vaccine to prevent HIV may need to stimulate immune responses that can act very quickly following infection, before the bulk of lymphocytes capable of countering the infection are lost, perhaps irreversibly."