amfAR, The Foundation for AIDS Research

The HAART—and Gut—Of Acute HIV Infection

By Jeffrey Laurence, M.D.

January 22, 2007—Our intestinal tract harbors the largest collection of immune cells in the body. No wonder then that recent amfAR-funded research has identified these tissues as key targets of HIV infection. But surprisingly, they could also prove to be of critical importance in the design of novel AIDS treatments that, unlike current antiretroviral drugs, might restore immune function.

Writing in the December 2006 issue of the journal PLoS Medicine, Dr. Martin Markowitz and colleagues at the Aaron Diamond AIDS Research Center in New York described studies (funded by amfAR with the support of its partner Concerned Parents for AIDS Research) of 18 individuals who had begun treatment during acute HIV infection. It was assumed that if anyone could hope to protect their immune system against damage by HIV, it would be those initiating such early drug therapy. Biopsies of the patients’ colons were taken at different time points over the next 32 months and compared with similar samples from uninfected individuals and 22 patients who had begun antiretroviral treatment at later stages of infection.

But regardless of when treatment was started, none of the HIV-infected patients showed a return to normal levels of CD4+ T cell percentages in their gut. Just over two-thirds maintained a decrease of 50 percent or more in these T cells despite up to seven years of continuous antiretroviral therapy that completely suppressed detectable virus in their blood.

Markowitz and colleagues proposed several possible explanations for these findings. Chronic immune stimulation of gut T cells could lead to their early and inappropriate death by a process known as AICD, or activation-induced cell death. In fact, Dr. Daniel Douek, a former amfAR grantee and current member of its Scientific Advisory Committee, noted in a paper published in the December 2006 issue of Nature Medicine that an ominous cycle may be established early after an HIV infection. He posits that the protective role of the cells that line the intestine is disrupted early in infection, permitting bacterial products that normally reside in the intestine to enter into the blood. These bacterial products then activate new T cells, targeting them for destruction by AICD.

Given all this damage, can we ever hope to achieve true immune reconstitution in AIDS? Dr. Markowitz urged caution, noting that, “Although clinically silent over the short term, the long-term consequences of the persistence of this lesion may emerge as the HIV-1-infected population survives longer owing to the benefits of HAART.” But he also noted that studies of monkeys infected with the simian AIDS virus, SIV, suggest that an immune hormone, IL-15, may stimulate production of the types of T cells lost early in HIV infection, and promote their transport to the gut.

More research is needed into measuring the effectiveness of individual anti-HIV drugs in the intestines, in the understanding of the process by which mobile CD4+ T cells locate their appropriate position there, and in determining how bacterial products released by a damaged intestine might maintain an inappropriate state of T cell activation and death. These areas are topics of current, and future, amfAR funding.

Dr. Laurence is amfAR’s Senior Scientific Consultant.