An 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 at 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.
http://www.medpagetoday.com/HIVAIDS/HIVAIDS/43520
The process is "much more of a cellular suicide than a viral murder," according to Warner Greene, MD, PhD, of the Gladstone Institutes at 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.
http://www.medpagetoday.com/HIVAIDS/HIVAIDS/43520