Oct. 2, 1997 WINSTON-SALEM -- In what could be the most exciting advance in the treatment of AIDS to date, Bowman Gray School of Medicine scientists today reported a novel way to block the deadly HIV virus from ever invading white blood cells.
This new strategy, described in the Oct. 1 issue of the journal Nature Medicine, points to a fundamental new way to treat patients with HIV-1 infection or patients with Acquired Immune Deficiency Syndrome (AIDS).
This study, by Si.-Yi Chen, M.D., Ph.D., assistant professor of cancer biology, and his colleagues at Bowman Gray School of Medicine, describes how a critical co-receptor on the surface of particular white blood cells called lymphocytes is blocked, making the cells immune to infection by HIV-1.
HIV-1 virus causes AIDS by invading and destroying the white blood cells whose functions are essential to maintain the human immune system.
Chen's advance is based on the recent discovery of the critical role of chemokine receptors on the surface of the lymphocyte, as the doorway B or co-receptor B for the HIV invasion into lymphocytes.
After virus invasion, the now familiar steps in the development of AIDS follow: multiplication of the virus in the infected cells and the killing of the infected cells, progeny virus spreading to other normal lymphocytes, the decline of the disease-fighting CD4 lymphocytes and the progression to AIDS, and its ultimate downward spiral.
Last year, in another dramatic discovery, a genetic defect in a chemokine coreceptor was found to protect individuals with this defect from HIV-1 infection. These genetically defective individuals remain healthy, because the usual functions of a defective chemokine receptor can be taken over by other receptors because of redundancies in the chemokine family.
So, Chen reasoned, "genetic inactivation of the chemokine co-receptors should protect lymphocytes from HIV-1 infection and have therapeutic implications."
Chen and his colleagues set out to mimic the natural resistance of the genetically defective individuals. They designed a novel approach, termed "intracellular chemokine" -- intrakine for short -- to genetically inactivate a CXC-chemokine coreceptor, or CXCR4 for short. This CXCR4 co-receptor plays a critical role in HIV-1 fusion and entry into permissive cells, especially for T-cell line tropic HIV-1 viruses that are frequently isolated in late stages of HIV-1 infection and AIDS.
In their studies, Chen and his colleagues were able to inactivate CXCR4 through a series of steps B steps that prevent newly-produced CXCR4 deep within the lymphocyte from ever reaching the cell surface. The key is the alteration of what is known as the SDF-intrakine, which binds to the CXCR4 and traps the molecules inside the lymphocyte.
Hence there is no place on which the HIV-1 virus can land to infect the cell.
"The genetically modified lymphocytes are immune to T-tropic virus infection but appear to maintain normal biological activities," he said.
Chen said that in treating people with AIDS or HIV infection, if the process proves out, human lymphocytes would be removed from an infected patient, genetically modified with intrakine, and periodically reinfused back into patients to delay or prevent the disease progression.
"This intrakine strategy likely is superior to currently described anti-HIV approaches," said Chen, for two main reasons:
* The intrakine approach is aimed at preventing virus entry into the cell, rather than interfering with virus multiplication. Therefore, the lymphocytes protected by this approach would be truly virus-free. In contrast, all other currently described genetically based anti-HIV-1 approaches can only inhibit virus multiplication after virus infection. * This anti-HIV-1 intrakine targets a cellular chemokine receptor, rather than HIV-1 viral components. "This approach may provide a new paradigm for the treatment of HIV-1 infection, that is, to protect cells from HIV-1 infection, rather than to inhibit HIV-1 replication," Chen said. "As long as this approach can protect sufficient amounts of lymphocytes to maintain immune functions, the HIV-1-infected individuals would be healthy, even if HIV-1 viruses still replicate in the individuals." He said that since genetically modified lymphocytes can live for many months or years, "this gene-based intrakine therapy should have a potent and long-lasting anti-HIV effect."
In contrast to Chen's approach, the best current HIV treatment is with combinations or "cocktails" of drugs. While these combinations of medications shows promise of extending the lives of patients with HIV-1, Chen said, "such an approach induces toxic side effects, selects for resistant mutants, and is unlikely to completely eliminate HIV-1 from infected individuals."
Chen said, "A strategy of genetic modification of host cells, the lymphocytes or stem cells, for resistance to HIV-1 infection, together with drug therapy, may hold the ultimate hope for HIV treatment."
His group is now in the stage of pre-clinical study to further evaluate the efficacy and safety of this intrakine approach. But he said clinical trials in people are a year or more away.
The research scientists in Chen's team include Jidai Chen, M.D., Ph.D. and An-gang Yang, M.D., Ph.D. both post-doctoral fellows, and Xuefai Bai, Ph.D., a research fellow.
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