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In HIV infection, HAART little help to gut immune cells

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In HIV Infection, HAART Little Help to Gut Immune Cells
  By Michael Smith, Senior Staff Writer, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine.
December 05, 2006

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. Action Points

Explain to interested patients that the success of highly active anti-retroviral therapy (HAART) is usually measured by examining the immune cells in the bloodstream.

Note that this study suggests that the immune system in the gut is also under assault by the virus and is less likely to benefit from HAART as currently constituted.
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."

 And from this site ;

Hey Ray,
I have wondered about this for some time. Given the results of this study and the other information provided by Tim Horn, I have to wonder if some gut issues we Hi-fivers face might not be a result of the ongoing battle in the mucosal tissue.

Many positives become lactose intolerant. While not itself unusual, could it be related?

There also is the propensity we positives have for malabsorption of nutrients.

As a celiac, I know my CD4 count in my mucosal tissue was already less than "normal." I wonder whether the artificial suppression of mucosal CD4s caused by celiac disease has allowed me to remain relatively healthy because it basically starved the HIV usually found in the gut, or at least kept it on a diet.

This is interesting and I look forward to learning more.



I've been thinking the same thing for a long time too, I remember seeing a photo of a healthy intestine next to a photo of the same intestinal region of an HIV positive person in a scientific american once. The differences were striking.

Does anyone know exactly what role CD4 cells play in the GI tract?

One theory is that they are part of the symbiosis that occurs in the gut. They are the predator that keeps the lambs at bay. Did you know that there are more microflora cells in your gut (anyones gut) than you have cells in your body? One thought is that when the predator is lost, the flora are free to fight it out. This leads to a loss in the balance and problems.


You guys are to technical for me. In laymans terms what other crap do we need to be on the lookout for while our id doc slaps us on the back and says the meds are working.

And are these additional issues a concern regardless of cd4 absolute and % .

thanks ( i think  ;)  )


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