Research led by scientists at the Gladstone Institutes, San Fransisco, United States has identified the precise chain of molecular events in the human body that drives the death of most of the immune system’s CD4 T cells as an HIV infection leads to AIDS. Further, they have identified an existing anti-inflammatory drug that in laboratory tests blocks the death of these cells — and now are planning a Phase 2 clinical trial to determine if this drug or a similar drug can prevent HIV-infected people from developing AIDS and related conditions.
Two separate journal articles, published simultaneously in Nature and Science, detail the research from the laboratory of Warner C. Greene, MD, PhD, who directs virology and immunology research at Gladstone, an independent biomedical-research non-profit. His laboratory’s science paper reveals how, during an HIV infection, a protein known as IFI16 senses fragments of HIV DNA in abortively infected immune cells. This triggers the activation of the human enzyme caspase-1 and leads to pyroptosis, a fiery and highly inflammatory form of cell death. As revealed in the Nature paper, this repetitive cycle of abortive infection, cell death, inflammation and recruitment of additional CD4 T cells to the infection “hot zone” ultimately destroys the immune system and causes AIDS. The Nature paper further describes laboratory tests in which an existing anti-inflammatory inhibits caspase-1, thereby preventing pyroptosis and breaking the cycle of cell death and inflammation.
“Gladstone has made two important discoveries, first by showing how the body’s own immune response to HIV causes CD4 T cell death via a pathway triggering inflammation, and secondly by identifying the host DNA sensor that detects the viral DNA and triggers this death response,” said Robert F. Siliciano, MD, PhD, a professor of Medicine at Johns Hopkins University, and a Howard Hughes Medical Institute investigator. “This one-two punch of discoveries underscores the critical value of basic science — by uncovering the major cause of CD4 T cell depletion in AIDS. Dr Greene’s laboratory has been able to identify a potential new therapy for blocking the disease’s progression and improving on current antiretroviral medications.”
The research comes at a critical time, as so-called AIDS fatigue leads many to think that HIV/AIDS is solved. In fact, HIV infected an additional 2.3 million people last year, according to UNAIDS estimates, bringing the global total of HIV-positive people to 35.3 million. Antiretroviral medications (ARVs) can prevent HIV infections from causing AIDS, but they do not cure AIDS. Further, those taking ARVs risk both a latent version of the virus, which can rebound if ARVs are discontinued, and the premature onset of diseases that normally occur in aging populations. Plus, some 16 million people who carry the virus do not have access to ARVs, according to World Health Organization estimates.
Seeking solutions for all these challenges, the new Gladstone discovery builds on earlier research from Dr. Greene’s lab, published in Cell in 2010. This study showed how HIV attempts, but fails, to productively infect most of the immune system’s CD4 T cells. In an attempt to protect the body from the spreading virus, these immune cells then commit “cellular suicide,” leading to the collapse of the immune system — and AIDS.
After that research, the Gladstone scientists began to look for ways to prevent this process by studying exactly how the suicidal response is initiated. Working in the laboratory with human spleen and tonsil tissue, as well as lymph-node tissue from HIV-infected patients, the researchers found that these so-called abortive infections leave fragments of HIV’s DNA in the immune cells. As described in Nature, pyroptosis ensues as immune cells rupture and release inflammatory signals that attract still more cells to repeat the death cycle.
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