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Commentary & Opinion
New HIV/AIDS Research Directions Show Promise, NEJM Editorial Says

February 12, 2009

Some recent HIV/AIDS research that examines the role certain genes play in inhibiting HIV progression shows promise for the development of new treatment measures, Jay Levy of the University of California-San Francisco writes in an editorial published Thursday in the New England Journal of Medicine. According to Levy, research has identified certain HIV-positive people who do not take antiretroviral drugs and still do not progress to AIDS for more than 10 years. In addition, some people remain HIV-negative even after repeated exposure to the virus, he writes. According to Levy, these "long-term survivors and those who have been exposed to HIV but remain seronegative offer a great opportunity to study the mechanisms of resistance to HIV infection and disease."

Levy writes that HIV enters the body through CD4+ T cells and then binds to the chemokine receptors CCR5 and CXCR4. While "X4 HIV types use CXCR4," R5 HIV, the most "predominant virus detected after transmission," uses CCR5. He continues that research has found that people whose cells lack expression of the CCR5 gene typically demonstrate resistance to the virus, even after repeated exposure to R5 HIV. According to Levy, about 1% to 3% of the population in Western countries carries the CCR5 mutation. In addition, among people with a single copy of the CCR5 gene, HIV appears to progress slower, he writes. Levy adds that "such information is of value in efforts to develop new approaches for therapy."

Levy describes a study published in the same issue of NEJM by Gero Hutter and colleagues, which illustrates "an innovative approach that could prove beneficial for the long-term control of HIV without antiretroviral therapy." For the study, researchers examined the case of an HIV-positive patient with myelogenous leukemia who received a bone marrow transplant from a person whose cells lacked expression of the CCR5 gene. After two transplants, the researchers determined that the patient had no leukemia recurrence and no detectable level of HIV in the bloodstream. In addition, the patient's T cell levels after two years returned to a normal range, and the patient's cells carried the donor's CCR5 mutation. Levy writes, "Although some observers may consider the patient cured of HIV, this conclusion is premature." He explains that HIV can persist in the lymph nodes and other parts of the body. However, "the result of this study and others provide further encouragement for those examining approaches to treatment that reduce CCR5 expression in persons with HIV."

Despite the promising results of the Hutter study, several challenges remain for developing effective HIV treatments based on the research, Levy writes, adding that an "X4 type of HIV ... could eventually emerge" because this "virus grows in cells lacking CCR5 expression." In addition, "people lacking the CCR5 gene can be more susceptible to serious effects from certain infections," according to Levy. He continues that "many patients die" from bone marrow transplants and administering manipulated stem cells "carries a similar risk." Therefore, "an approach designed to modify HIV target cells without eliminating the host's own bone marrow could be helpful," he writes. According to Levy, one example would be to inject an HIV-positive person with a biochemical compound or genetic vector that inactivates the CCR5 gene. He writes, "Although such techniques need to be perfected, they point in directions that may serve as stimuli for other innovative gene therapies" to treat HIV-positive people. Levy writes that the case described in Hutter's study "places further emphasis on gene therapies and treatments directed at blocking the CCR5 receptor," concluding that the study "could pave the way for innovative approaches that provide long-lasting viral control with limited toxicities for persons with HIV" (Levy, NEJM, 2/12).

Online The editorial is available online. The Hutter study also is available online.

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