How HIV Destroys Immune Cells

During HIV infection, CD4 T cells in lymphoid tissues initiate a highly inflammatory form of cell death that helps cripple the immune system.

HIV leads to AIDS primarily because the virus destroys essential immune cells called CD4 T cells, but precisely how these cells are killed has not been clear. Two papers published simultaneously on December 19th in Nature and Science reveal the molecular mechanisms that cause the death of most CD4 T cells in lymphoid tissues, the main reservoir for such cells, during infection.

Two research teams led by Warner Greene at the Gladstone Institutes in San Francisco have demonstrated that the vast majority of CD4 T cells in lymphoid tissues, despite their ability to resist full infection by HIV, respond to the presence of viral DNA by sacrificing themselves via pyroptosis—a highly inflammatory form of cell death that lures more CD4 T cells to the area, thereby creating a vicious cycle that ultimately wreaks havoc on the immune system.

“It’s really elegant science,” said Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases at the National Institutes of Health (NIH) in Bethesda, Maryland, who was not involved in the research. “It goes a long way to explaining what has been an enigma for practically 30 years.”

Richard Koup, who leads the immunology lab at the Vaccine Research Center at the NIH, agreed: “For years we’ve just said ‘HIV infects the cells and kills them,’ but it’s clearly more complicated than that. These papers start to delineate the multiple different mechanisms that HIV might have to kill CD4 T cells.”

“This cell-death pathway links the two signatures of HIV disease progression—that is, CD4 T cell-depletion and chronic inflammation—for the first time,” added Greene, who directs the Gladstone Institute of Virology and Immunology. What’s more, an existing anti-inflammatory drug can block the pathway, raising the prospect of new therapies that target the host response rather than the virus. 

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