HIV Lingers in Gut Despite HAART

SACRAMENTO, Calif., July 31 -- Even when HIV has all but disappeared from the peripheral blood after the start of therapy, the virus may still be lurking in the gut, slowing the restoration of immune response, according to researchers here.

The gut-associated lymphoid tissue (GALT) -- which accounts for about 70% of the body's immune system -- is an important site for early HIV replication, associated with severe depletion of CD4-positive T-cells, said Satya Dandekar, Ph.D., of the University of California at Davis.

And despite the apparent success of highly active antiretroviral therapy (HAART) in suppressing the virus -- as measured in the blood -- some patients may still have active infection in gut-associated lymphoid tissue, Dr. Dandekar and colleagues reported in the August issue of Journal of Virology.

"This is the first longitudinal study to show that while current HIV therapy is quite successful in reducing viral loads and increasing T-cells in peripheral blood, it is not so effective in gut mucosa," Dr. Dandekar said. "We need to be focusing our efforts on improving treatment of gut mucosa, where massive destruction of immune cells is occurring."

An associated finding is that inflammation may play a role in slowing the restoration of immune function in gut-associated lymphoid tissue, she and colleagues said.

In a small, longitudinal study, the researchers tracked the effect of HAART on three patients treated soon after their infection and on seven patients who had begun therapy for chronic disease. They found:

• All patients had a rapid decline in HIV viral loads and a corresponding increase in CD4 cells in the peripheral blood, although the response was quicker in those with a primary infection.
• Six months after the start of HAART, viral loads in gut-associated lymphoid tissue were undetectable in those with primary infection and remained so, but the seven chronic patients had incomplete suppression.
• At the same time, restoration of mucosal CD4 cells was slow in both groups.

"We found a substantial delay in the time that it takes to restore the gut mucosal immune system in those with chronic infections," Dr. Dandekar said. "In these patients the gut is acting as a viral reservoir that keeps us from ridding patients of the virus."

One key factor, she said, is to begin HAART quickly, because the patients with primary infection did better in this study than those treated after some months or years of HIV infection.

DNA microarray techniques may have pinpointed another factor, the researchers said. Analysis showed that patients who responded quickly to therapy tended to have up-regulation of genes involved in growth and repair in the gut, while those who responded poorly tended to have activity in genes associated with stress and inflammation.

The finding suggests that anti-inflammatory drugs might be beneficial in addition to HAART, Dr. Dandekar said.

The researchers are following additional patients, and data on them, although unpublished, support the current findings, according to Thomas Prindiville, M.D., of UC Davis, a co-author. "What we continue to see is that restoration of immune function is more likely when treatment is started early," he said.

Dr. Prindiville said the current standard for starting HAART -- waiting until T-cell counts fall below 350 per cubic millimeter of blood -- should be re-thought, given that early treatment did better in clearing the gut-associated lymphoid tissue infection.

"If we are able to restore the gut's immune response, the patient will be more likely to clear the virus," Dr. Prindiville said. "You can't treat any infectious disease without the help of the immune system."