Since the beginning of the AIDS epidemic in the 1980s, even before the HIV virus was identified, physicians and scientists recognized that a cardinal feature of AIDS was the loss of CD4+ T cells. These cells are killed by direct HIV infection but researchers have remained puzzled as to why uninfected CD4+ T cells also die in HIV-infected patients.
Researchers at the Institut de Biologie in France have now shown that an HIV surface glycoprotein expressed by HIV-infected CD4+ T cells interacts with a receptor known as CXCR4 on the surface of uninfected CD4+ T cells, which triggers a cell signaling pathway known as autophagy, resulting in the death of uninfected T cells. The study appears in the August issue of the Journal of Clinical Investigation.
Martine Biard-Piechaczyk and colleagues co-cultured HIV-infected CD4+ T cells that express the HIV envelope glycoprotein with uninfected target cells that express CD4 and the CXC chemokine receptor CXCR4. They found that CXCR4 engagement by the HIV envelope glycoprotein activates the degradation pathway known as autophagy, causing the death of these uninfected "bystander" cells.
The authors go on to show that molecules known as "short interfering RNAs" specific for two different genes involved in the autophagy pathway (beclin1 and atg7) can completely block the cell death process triggered by CXCR4 engagement by the HIV envelope glycoprotein.
In an accompanying commentary, Beth Levine from University of Texas Southwestern Medical Center discusses how this work eloquently establishes a mechanism for how the number of uninfected CD4+ T cells is likely depleted in patients with AIDS.
Materials provided by Journal of Clinical Investigation. Note: Content may be edited for style and length.
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