Additional treatment strategies needed to completely eliminate HIV reserves

Photo of Satya Dandekar
Satya Dandekar, professor and chair of the department of medical microbiology and immunology .

For the thousands of patients with AIDS, the arrival of highly active antiretroviral therapy (HAART) in 1997 was a godsend. The treatment, which prevents HIV replication and the subsequent viral invasion of the body's T cells, has cut death rates and extended the lives of HIV patients for many years.

But the research of Satya Dandekar, professor and chair of the Department of Medical Microbiology and Immunology, and her team at UC Davis has shown that patients could benefit even more if treatment efforts were focused on monitoring and treating the high levels of HIV that hide in the mucosal tissue of the gastrointestinal track. The results of her most recent study were published in the August 2006 issue of the Journal of Virology.

"Our study showed that despite current drug therapies, the human immunodeficiency virus is able to survive in the mucosal tissues of the gut, where it continues to replicate and suppress immune system function,” she said. “This is especially true for patients with chronic infections because the gut is acting as a viral reservoir that prevents us from completely eliminating the virus. With the real battle between the virus and exposed individuals happening in the gut immediately after viral infection, we need to be focusing our efforts on improving treatment of gut mucosa, where massive destruction of immune cells is occurring.”

Dandekar believes patients being treated with antiretroviral therapy should be monitored with gut biopsies, instead of just measures of T-cells circulating in the peripheral blood, and recommends restoring the gut's immune function by introducing antiretroviral treatments earlier and prescribing anti-inflammatory medications.

Physicians treating HIV-infected patients have long relied on blood measurements of viral load and T-cell counts when choosing a course of treatment. Viral load is the number of viral particles in a milliliter sample of blood. T-cell counts reflect the number of CD4+ T-cells in the sample. These cells, also called T-helper cells, organize the immune system's attack on disease-causing invaders. They are, however, the targets of the virus and their numbers decrease as the amount of HIV increases, leaving the body vulnerable to a variety of infections.

Last year, Dandekar's team published a study of HIV-infected patients who, despite the lack of treatment, had survived over 10 years with healthy levels of T-cells 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 outcome,” Dandekar explained.

Those results prompted Dandekar and her team to undertake the current study, in which they set out to evaluate the effect of highly active antiretroviral therapy, known as HAART, on viral suppression and immune restoration in gut-associated lymphoid tissue. They followed 10 patients being treated with HAART, taking blood and gut samples before and after three years of treatment. Three of the patients were treated during four to six weeks of first being infected with the virus. The other participants were known to be HIV positive for more than one year.

Photo of fluorescence immunohistochemistry to detect and localize the CD4+ T cells repopulating the gastrointestinal tract of patients during HAART.
Researchers used fluorescence immunohistochemistry to detect and localize the CD4+ T cells repopulating the gastrointestinal tract of patients during HAART. The top two photos show the distribution of CD4+ T cells (yellow) in the intestine of one healthy patient (left) and severe CD4+ T cell depletion in one HIV-infected patient prior to HAART. The bottom two photos show that scattered repopulation of CD4+T cells in the intestinal mucosa occurred only modestly after long term therapy. (View each photo individually: HIV-negHIV-naiveHIV-6 moHIV_3 yrs) 

Hoping to figure out why HAART does not work as well in the gut, Dandekar and her colleagues further examined the post-treatment of gut-associated lymphoid tissue samples. They found evidence of inflammation, which disrupts tissue function, promotes cell death and upsets the normal balance of gut flora. They also found that the activity of genes that control and promote mucosal repair and regeneration were suppressed, while the genes responsible for the inflammatory response were more active than in normal tissue.

Dandekar said these results suggest anti-inflammatory drugs may improve antiretroviral treatment outcomes. She also pointed out that genes involved with the repair and regeneration of gut-associated lymphoid tissue would make excellent drug targets.

Researchers then compared HAART outcomes in those who chose to be treated within the weeks of exposure to those with chronic infection. They discovered that newly infected patients had fewer signs of inflammation at the beginning of the study and experienced greater recovery of the gut mucosal immune system function by the end of it.

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

The team of physicians and researchers plan to keep testing ways of improving the efficacy of antiretroviral therapy in gut-associated lymphoid tissue. These include treating gut inflammation, starting treatment earlier and using gut biopsies to monitor treatment success.

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