Wake Forest Scientists Find Way To Short-Circuit Initial HIV Invasion

In a report in the Oct 14 issue of the Proceedings of the NationalAcademy of Sciences, Si.-Yi Chen, M.D., Ph.D., assistant professor of cancerbiology, and his colleagues describe how they have inactivated the mostfrequently used co-receptor -- docking site -- for HIV-1 viruses on the surfaceof both macrophages and lymphocytes, resulting in immunity of those macrophagesand lymphocytes to HIV-1 infection.

This co-receptor is called CCR5 and serves as the doorway or dockingsite for early-stage HIV-1 virus, known scientifically as macrophage tropic (orM-tropic) virus.

Two weeks ago, the same team reported in Nature Medicine that they hadfound a way to inactivate a different co-receptor -- CXCR4 -- which is thedocking 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-tropicor T-cell tropic. During the period soon after HIV-1 infection when mostpatients have no symptoms, most HIV-1 viruses are M-tropic, and use the CCR5co-receptor for entry into lymphocytes and macrophages.

In the late stage of AIDS, HIV-1 viruses change their infectivity toT-cell tropic, and use the CXCR4 receptor to get into the lymphocytes. Soblocking entry of that type of virus into the cell blocks the late stages ofAIDS.

The approach described in Nature Medicine could be utilized to treatAIDS patients and late stage HIV-1-infected individuals, while the approachdescribed in Proceedings could be used to treat early-stage of HIV-infectedindividuals 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 geneticallyinactivate the chemokine co-receptor.

In the report in Proceedings, Chen and his colleagues described how theyused an intrakine called RANTES-intrakine to successfully inactivate the CCR5co-receptor for the macrophage-tropic HIV-1 viruses..

The SDF-intrakine described in Nature Medicine genetically inactivatesthe CXCR4 co-receptor. The SDF-intrakine binds to the CXCR4 and traps themolecules inside the lymphocyte, leaving the T-cell tropic HIV-1 with no placeto dock.

Chen said that the intrakine approach avoids technical problems facingmany current gene therapy approaches.

"This intrakine approach is especially well suited to be translatedinto clinical practice," Chen said, noting that on a typical macrophage orlymphocytes, there are few CCR5 co-receptors, which means that the task ofinactivating the CCR5 can be achievable by current available gene therapytechnology. Intrakines are human derivatives, and not foreign to human.

In treating people with HIV infection, Chen envisions that in the nearfuture, human macrophages and lymphocytes from an infected patient's peripheralblood can be genetically modified with the appropriate intrakine, andperiodically reinfused back into patients to delay the disease progression.

Ultimately, Chen said he hoped that stem cells, the mother cells of allimmune cells with an unlimited capability of proliferation, can be geneticallymodified with the intrakine, and reinfused back into patients to regenerate anew immune system that is resistant to HIV-1 infection.

His group is now in the stage of pre-clinical study to further evaluatethe efficacy and safety of this intrakine approach, and clinical trials inhumans are a year or more away.

The Proceedings article was edited by Anthony S. Fauci, M.D., directorof the National Institute of Allergy and Infectious Diseases of NIH, and and amember of the editorial board. The research scientists in Chen's team includeAn-gang Yang, M.D., Ph.D. a post-doctoral fellow, Xuefai Bai, Ph.D., a researchfellow, and Xue F. Huang, Ph.D. a research fellow.