The nationwide experiment will initially include around 100,000 volunteers.
During HIV infection, CD4 T cells in lymphoid tissues initiate a highly inflammatory form of cell death that helps cripple the immune system.
December 19, 2013|
FLICKR, NIAIDHIV 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 today (December 19) 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.
The death of CD4 T cells during HIV infection has generally been attributed to plain old apoptosis, or programmed cell death. Problem is, most studies have focused on active cells in the blood, which are “productively infected” by HIV, meaning that the virus has integrated with host-cell genome and can make copies of itself. In a 2010 study, Greene and his colleagues showed that 95 percent of CD4 T cells in lymphoid tissue, by contrast, are bystander cells that are “abortively infected”—the virus penetrates but can’t integrate or replicate. To better understand HIV pathogenesis, Greene sought to figure out how this particular population of immune cells dies during HIV infection.
For the study published in Nature, the team looked at human spleen and tonsil tissue cultured in the lab and spiked with HIV. The researchers found that when the virus productively infects the few permissive CD4 T cells present, death occurs through apoptosis mediated by an enzyme called caspase-3. But when HIV abortively infects nonpermissive CD4 T cells, death occurs by pyroptosis, which depends on the activation of caspase-1. It turns out that the vast majority—roughly 95 percent—of CD4 T cell death in lymphoid tissues is driven by caspase-1-mediated pyroptosis.
In bacterial infection, the release of inflammatory signals is thought to promote clearance by attracting more immune cells to help. In a pathogenic inflammation scenario like HIV infection, however, the strategy backfires. Instead of clearing the infection, proinflammatory signals released by pyroptosis attract more cells into the infected tissue to die and, in turn, produce more inflammation. “The cavalry come riding in and fall victim to this same form of fiery cell death, turning their rifles on themselves,” says Greene.
In the Science study, Greene and colleagues used a technique called DNA affinity chromatography to identify proteins in the CD4 T cells that detect fragments of HIV DNA and alert the enzyme caspase-1. They identified six candidates that all bind HIV DNA, including one called IFI16, which is known to be part of the protein complex that initiates inflammatory immune responses. And when they genetically manipulated CD4 T cells to knock out IFI16, the researchers were able to inhibit pyroptosis.
The discoveries could help researchers come up with new treatments that restrain the hosts’ destructive response to HIV rather than the virus itself. The authors showed in the Nature study that an existing caspase-1 inhibitor—a drug already shown to be safe in humans—suppressed CD4 T-cell death and inflammation in cell culture. They are now planning a Phase II clinical trial to test its capacity to block pyroptosis in HIV-infected patients.
Fauci said such an approach would not replace antiretrovirals (ARVs), which suppress HIV replication and halt disease progression. But it could be used in combination in people who are dealing with highly resistant HIV strains to reduce the destruction of CD4 T cells and inflammation. “One of the things about blocking the host response is that it's very difficult for the virus to mutate to counteract it,” added Fauci.
Greene pointed out that a caspase-1 inhibitor might also provide a bridge therapy for the millions of people without access to ARVs. He added that such drugs might even prevent expansion of the reservoir of latent virus that lies low in memory CD4 T cells, which has so far precluded a cure for HIV/AIDS.
The dysregulated action of cytokines during chronic inflammation might stimulate the homeostatic proliferation of memory CD4 T cells. “If we get rid of chronic inflammation, will we stop the homeostatic proliferation and degrade the latent reservoir?” asked Greene. “That’s something we can test. If it does, caspase-1 inhibitors might—and I emphasize might—become a component of a curative cocktail.”
G. Doitsh et al., “Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection,” Nature, doi:10.1038/nature12940, 2013.
K. M. Monroe et al., “IFI16 DNA sensor is required for death of lymphoid CD4 T cells abortively infected with HIV,” Science, doi:10.1126/science.1243640, 2013.