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 thenelli01

New discovery on HIV/AIDS

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Gladstone’s discovery of precise molecular mechanisms in the human body leads to a new potential therapy for our era’s deadliest epidemic
 
By GLADSTONE STAFF
 
December 19, 2013—To repair a racecar, it helps to know how the engine works. The same is true in biology, where research into the precise molecular mechanisms that operate the human body—in sickness and in health—can be key to finding new preventions, treatments and cures for disease.

New research from the laboratory of Warner C. Greene, MD, PhD, at the Gladstone Institutes underscores this notion by revealing the body's step-by-step reaction to an HIV infection. The lab’s discovery of exactly how the body—and not the virus—kills most of the immune system’s CD4 T cells has helped the lab identify a potential new therapy that may block AIDS. A Phase 2 clinical trial is being planned.

“Our studies have investigated and identified the root cause of AIDS—how CD4 T cells die,” said Gladstone Staff Research Investigator Gilad Doitsh, PhD. Dr. Doitsh has been spearheading this research for years in the laboratory of Dr. Greene, who directs virology and immunology research at Gladstone, an independent biomedical-research nonprofit. “Despite some 30 years of research into the virus, this key HIV/AIDS process has remained pretty much a black box.”

 

The research could hardly come at a more critical time, as something referred to as AIDS fatigue leads many to think that HIV/AIDS is solved. In fact, HIV infected an additional 2.3 million people in 2012, 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 cureAIDS. Further, those taking ARVs risk both the premature onset of diseases that normally occur in aging populations, as well as a latent version of the virus that can rebound if ARVs are discontinued. Additionally, some 16 millionpeople who carry the virus lack access to ARVs, according to World Health Organization estimates.

The potential therapy identified by Dr. Greene’s lab may offer effective solutions for all these challenges.

 

 

Building on Previous Research

As is often the case in science, this new work builds on an investigation that began years ago. Published in Cell in 2010, previous research that Dr. Doitsh also spearheaded showed how HIV attempts, but fails, to productively infect the vast majority of CD4 T cells. And in an attempt to protect the body from further spreading the virus, these immune cells commit “cellular suicide,” killing the immune system and causing AIDS.

After that research, Drs. Greene and Doitsh began to look for ways to prevent this by studying exactly how the suicidal response functions. Working in the laboratory with human spleen and tonsil tissue, as well as lymph-node tissue from HIV-infected patients, they found that these so-called abortive HIV infections leave fragments of the virus’s DNA in the immune cells.

As three lead authors—Dr. Doitsh, graduate student Nicole Galloway and Xin Geng, PhD—described inNature, these DNA fragments trigger a fiery and highly inflammatory form of cell death known aspyroptosis. During this process, immune cells rupture and release inflammatory signals that attract still more cells to repeat the death cycle. And again, using human tissue samples, they found that an existing, safe and well-tolerated anti-inflammatory drug that may be able to block this inflammation and pyroptosis in HIV-infected people.

“This identified IFI16 as the DNA sensor, which then sends signals to caspase-1 and triggers pyroptosis,” said Kathryn M. Monroe, PhD, the Science paper’s other lead author, who completed the research while a postdoctoral fellow at Gladstone. “We can’t block a process until we understand all of its steps—so this discovery is critical to devising ways to inhibit the body’s own destructive response to HIV. We have high hopes for the upcoming clinical trial.”This discovery, in turn, made the scientists wonder how the body senses the fragments of HIV’s DNA in the first place, before alerting an enzyme known as caspase-1 to launch an immune response. To identify the so-calledDNA sensor, the scientists found a way to genetically manipulate CD4 T cells in HIV-infected tissue. In doing so, they discovered that reducing the activity of a protein known as IFI16 inhibited pyroptosis, explained Zhiyuan Yang, PhD, a Gladstone postdoctoral fellow who is one of two lead authors of a Sciencepaper, published simultaneously with the Nature paper.

The Phase 2 trial being planned promises to validate a variety of expected advantages. For example, by targeting the human body, or host, instead of the virus, the drug is likely to avoid the rapid emergence of drug resistance that often plagues the use of ARVs. The anti-inflammatory may also provide a bridge therapy for the millions without access to ARVs, while also reducing persistent inflammation in HIV-infected people already on ARVs. Many suspect this inflammation drives the early onset of aging-related conditions such as dementia and cardiovascular disease. By reducing inflammation, the drug might also prevent expansion of a reservoir of latent virus that hides in the body and thwarts a cure for HIV/AIDS.

 

Full article: http://gladstoneinstitutes.org/node/11439

Edited by thenelli01

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The straight dope on the inception and early spread of HIV in the US is at last here. I had always doubted the Patient-0 story put about by Randy Shilts in And the Band Played On. Too convenient for making a good story, and it struck me as too conjectural. Always mistrust shortcut personifications of the complexities of real history, substituting for absent data.

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