Researchers Identify Mechanism By Which T Cells Resist Infection By HIV-1

April 10, 1997

Rockville, Maryland--Researchers have discovered that a new method of growing CD4+ T cells renders them resistant to HIV-1 infection by preventing the expression of a recently discovered coreceptor essential for HIV- 1 infection, as reported in today's issue of SCIENCE. The researchers, a collaborative team of virologists and immunologists from the Walter Reed Army Institute of Research, the National Institutes of Health, the Naval Medical Research Institute, and the Henry M. Jackson Foundation for the Advancement of Military Medicine, are led by Carl June, M. D. They had previously discovered that triggering the CD28 receptor on CD4+T cells promoted vigorous cell growth, as well as rendering the cells resistant to HIV- I infection. In the current study, the group demonstrated that when CD4+ T cells are stimulated through the CD28 receptor, entry of HIV-1 into the cell is blocked. They further demonstrated that the inability of HIV-1 to enter the cells is due to the lack of cell surface expression of a coreceptor for HIV-1 termed CCR5. These findings, which are in vitro, indicate that the basis for the HIV-1 resistance is similar to those individuals with a genetic lack of the CCR5 receptor. It is unknown how long the mutation retains its resistance after infusion. Last year researchers from the Aaron Diamond Institute reported that those individuals had a high level of resistance to infection with HIV-1 while maintaining healthy immune systems.

According to Dr. June, "the potential clinical importance of our finding is that this form of activation could lead to a class of drugs to prevent CCR5 expression in all individuals and eventually provide new vaccine and therapy strategies."

CCR5, identified in 1996, serves as a coreceptor for viruses typically found in the early, asymptomatic stages of HIV-1 infection. Another coreceptor, termed CXCR4/Fusin, discovered by Edward Berger and colleagues in 1996, is used by viruses obtained from individuals in the late stages of HIV- 1 infection, or by viral isolates that have been adapted to grow in T cell lines in the laboratory. While stimulation of the CD28 receptor does not prevent expression of CXCR-4/Fusin on the T cell surface, and hence infection by late stage HIV- 1 strains, the researchers are optimistic that this result may lead to other strategies by which coreceptor expression can be regulated. Formerly, it was believed that activation and growth of T cells necessarily lead to HIV- 1 susceptibility. These studies demonstrate that expression of coreceptors can be regulated in activated, growing T cells. It is likely that these observations could lead to the development of new therapeutic options for patients with HIV infection, as well as other immune deficiencies and cancer. Patients could receive infusions of CD4+ T cells, similar to blood bank transfusion procedures, thus possibly preventing the deterioration of immune function that accompanies HIV infection. This procedure could also have therapeutic utility for symptoms that result from HIV infection. A pilot clinical trial to test the safety and feasibility of this approach is currently underway.

The U.S. Military HIV Research Program is carried out under a cooperative agreement between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the U.S. Army Medical Research and Materiel Command.

The Henry M. Jackson Foundation is a private, not-for-profit organization chartered by Congress in 1983 to support medical research and education throughout the military medical community. The Foundation has collaborated on the U.S. Military HIV Research Program since its inception in 1988.

Henry M. Jackson Foundation for the Advancement of Military Medicine

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