31 July 2006

Intestines Act As HIV Reservoir

by Kate Melville

Gut-associated lymphoid tissue accounts for 70 percent of the body's immune system and should be a priority target for HIV treatments, claim University of California (UC) researchers. The researchers found that HIV hidden in gut mucosa suppresses the immune system and continues to replicate, despite standard tests indicating otherwise.

The study, published in the Journal of Virology, demonstrates how current methods of treating patients with the virus could be significantly improved. "This is the first 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," said Satya Dandekar, immunologist at UC Davis Health System.

It's common practice for doctors treating HIV-infected patients to rely on viral loads and T-cell counts when deciding upon a course of treatment. The viral load is measured by the number of viral particles in a milliliter of blood, while the T-cell count represents the number of CD4 T-cells (or T-helper cells) in the sample. T-cells direct the immune system's attack on invading bodies that cause disease, but these cells are themselves the targets of the HIV virus, and as the ratio of HIV to T-cells increases, the body is left open to all manner of infections.

In research conducted last year, Dandekar's team worked with untreated HIV-infected patients who had survived for over 10 years, and who had healthy T-cell levels and suppressed viral loads. "We looked at their gut lymphoid tissue and did not see loss of T-cells there. This correlated with better clinical outcomes," Dandekar explained. It was these observations that led to the recent evaluation of highly active antiretroviral therapy (HAART), and focused on why HAART was not effective in the gut.

Over a 3-year period the team took blood samples from 10 HIV-infected subjects being treated with HAART. The samples were taken both at the beginning and end of the 3-years. Three of the subjects received HAART 4-6 weeks after being diagnosed HIV positive, while the other subjects were already known to have been HIV positive for at least a year. The team found that the subjects who had been infected with the virus for a year or more had traces of inflammation known to disrupt tissue function, promote cell death and disturb the natural balance of gut flora. The team also found evidence among this group that the genes controlling mucosal repair and regeneration were suppressed, and that the genes associated with inflammation were unusually active. By comparison, the subjects treated early had less inflammation at the commencement of the trial, and showed significant recovery of gut mucosal immune system function by the trial's end.

"What we continue to see is that restoration of immune function is more likely when treatment is started early," said Thomas Prindiville, a gastroenterology professor at UC Davis and a co-author of the study. "Starting HAART before T-cell counts fall below 350 cells per cubic milliliter, would preserve immune function and hasten its full recovery."

The team's discovery highlights the importance of the gut during the initial stages of infection, as gut tissue represents a major component of the body's immune system. "The real battle between the virus and exposed individuals is happening in the gut immediately after viral infection," said Dandekar. "We need to be focusing our efforts on improving treatment of gut mucosa, where massive destruction of immune cells is occurring. Gut-associated lymphoid tissue accounts for 70 percent of the body's immune system. Restoring its function is crucial to ridding the body of the virus."

The results have led Dandekar to suggest a few new strategies designed to work in conjunction with existing treatments. She says that earlier antiretroviral and anti-inflammatory intervention would improve antiretroviral therapy outcomes, and that patients treated with antiretroviral therapy should be further monitored with gut biopsies. "We found a substantial delay in the time that it takes to restore the gut mucosal immune system in those with chronic infections," Dandekar said. "In these patients the gut is acting as a viral reservoir that keeps us from ridding patients of the virus." Dandekar added that the genes responsible for the repair and regeneration of gut-associated lymphoid tissue would be highly suitable drug targets.

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

Source: University of California, Davis - Health System