A new insight about how HIV kills

[HungLatinDom]

Suicide, not murder:

http://www.medpagetoday.com/HIVAIDS/HIVAIDS/43520

What's interesting here for me, is that shows that a fairly small amoun of cells are infected. If we knew how, we could nuke them and cure HIV. Some experimental therapies are focusing on this, but the big question was, how many remaining cells we would have.

This is the text of the article:

"In uncontrolled HIV infection, an over-the-top immune response causes much of the damage that leads to AIDS, researchers are reporting.

The process is "much more of a cellular suicide than a viral murder," according to Warner Greene, MD, PhD, of the Gladstone Institutes and the University of California San Francisco.

In papers in Nature and Science, Greene and colleagues outline -- for the first time -- how resting CD4-positive T cells die in response to HIV infection.

It's a "very new perspective," Greene told MedPage Today, and one that could very quickly lead to new therapeutic and perhaps even curative approaches.

The findings are a significant advance in the understanding of HIV pathophysiology, commented Demetre Daskalakis, MD, of Mount Sinai Hospital in New York City.

Even more than 30 years into the HIV/AIDS pandemic, he told MedPage Today, "it's remarkable that a lot is not known about how the very important cells in the immune system are actually depleted."

He added that it is likely that work will lead to advances in therapy. "Understanding HIV biologically is how you translate that to clinical innovation," he said.

HIV replicates by infecting activated CD4 T cells, which then produce copies of the virus and eventually die of programmed cell death, or apoptosis.

But if that were all, Greene said, they could easily be replaced by resting cells, which make up 95% of the targets encountered by the invading virus.

Instead, the resting cells also die, in what he called a "vicious pathological cycle."

In a series of experiments, he and colleagues show that the resting cells are the targets of "abortive infection," which cannot lead to fully formed HIV particles because the cells are not activated.

Instead, fragments of HIV DNA are scattered around the cell, eventually attracting the attention of a sensor molecule, interferon-gamma-inducible protein 16, or IFI16.

IFI16, the subject of the Science paper, initiates a process of cell death, mediated by the enzyme caspase 1 -- a molecule whose functions are the topic of the Nature paper.

Apoptosis in productively HIV-infected T cells, Greene and colleagues found, is mediated by another enzyme, caspase 3.

That form of cell death, Greene told MedPage Today, is a "very bland and silent process."

In contrast, the cell death of an abortively infected T cell -- dubbed pyroptosis -- is a dramatic event, spilling the cell's contents and proinflammatory cytokines, including interleukin-1β.

The result is inflammation, which draws more CD4 T cells to the area, where the HIV is waiting to repeat the process.

"It's as if the cavalry rode in and then turned their rifles on themselves," Greene said.

The good news is that blocking the activity of caspase 1 prevents the cell death and subsequent inflammation, at least in tissue experiments in the lab.

Moreover, at least one caspase 1 inhibitor -- a drug known as VX-765 -- is available and has been found safe and effective in clinical trials, albeit in epilepsy and psoriasis.

The researchers found that, in their tissue experiments, VX-765 effectively blocks caspase 1 activity, CD4 T cell death, and the release of interleukin-1β.

Greene said he and colleagues are working with the drug's maker and are eager to move into human trials in HIV.

If caspase 1 inhibitors prove as effective in the real world as in the lab, Greene said there is a range of possible uses.

In the developing world, he noted there are some 16 million people with HIV who do not have access to triple-drug antiretroviral therapy.

If a caspase 1 inhibitor were cheap, widely available, and easy to take, it might form a "sheltering place" -- slowing the progress of HIV while people waited for antiretroviral drugs.

Even for people with access to drugs, treatment is sometimes problematic because of resistance or other issues and caspase 1 blockers might be of value for them, Greene said.

Finally, there's evidence that inflammation drives the release of cytokines that in turn drive the proliferation of memory T cells.

Memory T cells form the so-called reservoir of HIV that allows it to return whenever antiretroviral therapy is stopped.

Caspase 1 inhibitors, he speculated, might be part of a cocktail of drugs that would lead to the "slow destruction" of the reservoir and the eventual clearance of HIV.

Indeed, that might be the most promising part of the research in the long term, Daskalakis commented.

"We know that the way to treat HIV is to give a full antiretroviral regimen," he said, and it's unlikely that caspase 1 inhibitors would replace that approach.

But the resting and memory cells are "the untapped targets" of HIV therapeutics. "If a cell is replicating actively, we know how to shut down HIV in that cell," he said. "But what we don't know ... is how to focus on depleting" the resting and memory cells.

A good understanding of that process might "really be the answer to drive the cure agenda," he said.

Greene also noted that people with HIV -- even if it is well-controlled -- have chronic inflammation that is thought to drive higher rates of other forms of illness, such as cardiovascular disease. Blocking caspase 1 might reduce that inflammation and prevent some of the so-called diseases of aging that appear to strike HIV-positive people earlier than others, he argued.

"If the biology leads us to a place where we can reduce inflammation," Daskalakis commented, "I think we're going to see better HIV outcomes with antiretrovirals.""

[firefighter]

Great article cheers for sharing HLD.