Oct. 14, 1997 WINSTON-SALEM -- Scientists at Wake Forest University Baptist Medical Center report today that they have found another way to shut down the doorway for HIV-1 to invade two types of white blood cells -- lymphocytes and macrophages.
In a report in the Oct 14 issue of the Proceedings of the National Academy of Sciences, Si.-Yi Chen, M.D., Ph.D., assistant professor of cancer biology, and his colleagues describe how they have inactivated the most frequently used co-receptor -- docking site -- for HIV-1 viruses on the surface of both macrophages and lymphocytes, resulting in immunity of those macrophages and lymphocytes to HIV-1 infection.
This co-receptor is called CCR5 and serves as the doorway or docking site for early-stage HIV-1 virus, known scientifically as macrophage tropic (or M-tropic) virus.
Two weeks ago, the same team reported in Nature Medicine that they had found a way to inactivate a different co-receptor -- CXCR4 -- which is the docking site for late stage HIV-1 virus, known medically as T-cell tropic virus.
Based upon HIV-1 infectivity, HIV-1 viruses are classified as M-tropic or T-cell tropic. During the period soon after HIV-1 infection when most patients have no symptoms, most HIV-1 viruses are M-tropic, and use the CCR5 co-receptor for entry into lymphocytes and macrophages.
In the late stage of AIDS, HIV-1 viruses change their infectivity to T-cell tropic, and use the CXCR4 receptor to get into the lymphocytes. So blocking entry of that type of virus into the cell blocks the late stages of AIDS.
The approach described in Nature Medicine could be utilized to treat AIDS patients and late stage HIV-1-infected individuals, while the approach described in Proceedings could be used to treat early-stage of HIV-infected individuals and may be some day be used to prevent HIV-1 infection.
For both instances, Chen and his colleagues designed a novel approach, termed "intracellular chemokine" -- intrakine for short -- to genetically inactivate the chemokine co-receptor.
In the report in Proceedings, Chen and his colleagues described how they used an intrakine called RANTES-intrakine to successfully inactivate the CCR5 co-receptor for the macrophage-tropic HIV-1 viruses..
The SDF-intrakine described in Nature Medicine genetically inactivates the CXCR4 co-receptor. The SDF-intrakine binds to the CXCR4 and traps the molecules inside the lymphocyte, leaving the T-cell tropic HIV-1 with no place to dock.
Chen said that the intrakine approach avoids technical problems facing many current gene therapy approaches.
"This intrakine approach is especially well suited to be translated into clinical practice," Chen said, noting that on a typical macrophage or lymphocytes, there are few CCR5 co-receptors, which means that the task of inactivating the CCR5 can be achievable by current available gene therapy technology. Intrakines are human derivatives, and not foreign to human.
In treating people with HIV infection, Chen envisions that in the near future, human macrophages and lymphocytes from an infected patient's peripheral blood can be genetically modified with the appropriate intrakine, and periodically reinfused back into patients to delay the disease progression.
Ultimately, Chen said he hoped that stem cells, the mother cells of all immune cells with an unlimited capability of proliferation, can be genetically modified with the intrakine, and reinfused back into patients to regenerate a new immune system that is resistant to HIV-1 infection.
His group is now in the stage of pre-clinical study to further evaluate the efficacy and safety of this intrakine approach, and clinical trials in humans are a year or more away.
The Proceedings article was edited by Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases of NIH, and and a member of the editorial board. The research scientists in Chen's team include An-gang Yang, M.D., Ph.D. a post-doctoral fellow, Xuefai Bai, Ph.D., a research fellow, and Xue F. Huang, Ph.D. a research fellow.
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