May 5, 2004 Massachusetts General Hospital (MGH) researchers may have provided another clue to the mystery of how HIV, the virus that causes AIDS, evades the defenses of the immune system. In the May issue of the Journal of Virology, a team from the Partners AIDS Research Center at MGH describes finding how a key protein that helps the virus enter its target T helper cells may also keep away the T killer cells that should destroy HIV-infected cells.
“One of the big questions in understanding HIV is why we can see immune responses that are effective in the test tube but do not eradicate the virus in the infected patient,” says Mark Poznansky, MD, PhD, of the Partners AIDS Research Center (PARC) and the MGH Infectious Disease Unit, the paper’s senior author. “We have identified a potential new mechanism by which pathogens can repel immune cells and thereby evade the immune system.”
In 2000, Poznansky and colleagues published a report that found how a protein called SDF-1, known to attract immune cells, can actually repel T cells when present in elevated quantities. SDF-1 is a chemokine, a protein normally produced to summon immune cells to the site of an injury or infection. The molecule is known to interact with a T cell receptor called CXCR4 which also is used by HIV when it binds to and enters T helper cells. Investigating whether HIV infection involves the same kind of cellular repulsion observed in the earlier study – a process the researchers dubbed “fugetaxis” – seemed a logical next step.
In a series of experiments led by Diana Brainard, MD, a research fellow in Poznansky’s lab, the team first found that while low concentration of gp120, the HIV protein that interacts with CXCR4, attracted T killer cells, higher concentrations induced the immune cells to move away. They then showed that it was the specific interaction of gp120 with CXCR4 that controlled T cell movement, and that the same repulsion could be produced specifically with T killer cells programmed to attack HIV.
The researchers then used immunized mice to look at the effects of the viral protein in vivo. One day after the mice were injected with an antigen to which they had been previously immunized, they received an additional injection of either low- or high-dose recombinant gp120 protein or saline as a control. For up to 24 hours afterwards, mice receiving the high-dose gp120 were found to have a significantly lower immune response to the antigen injection than either control mice or those that had received the low-dose gp120.
“This is the first report of fugetaxis caused by a viral gene product and could be an important way that HIV keeps the immune system at bay,” Poznansky says. “We don’t know yet if this process occurs in patients infected with HIV, but if it does, it provides a new therapeutic approach that could block this viral protein activity and allow immune cells to do their job.”
Brainard and Poznansky add that this mechanism could also be used by other viruses – including the pox viruses, papilloma viruses and herpes viruses – that remain in the body after initial infection and have proteins known to influence cellular movement. Poznansky is an assistant professor of Medicine at Harvard Medical School.
Additional co-authors are William Tharp, Elva Granado, Nicholas Miller, Alicja Trocha and Bruce Walker, MD, of MGH/PARC; Xiang-Hui Ren, MD, and Ernest Terwilliger, PhD, of Beth Israel Deaconess Medical Center; Brian Conrad, University of Michigan; and Richard Wyatt, Dana Farber Cancer Institute. The work was supported by grants from the U.S. Public Health Service and the American Foundation for AIDS Research.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $400 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, medical imaging, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Women’s Hospital joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services.
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