| |
How HIV Destroys Immune Cells, Blocking HIV Cell Death with Vertex Drug- 2 new studies. Scientists Discover How Key Immune Cells Die During HIV Infection and Identify Potential Drug to Block AIDS
|
| |
| |
Download the PDF Here
Download the PDF Here
"In the latest studies, Greene's team investigated these 'abortive' infections. They identified a sensor that detects viral DNA in the cell and activates the suicide response1. And they found that most of the cellular suicide occurs via a process called pyroptosis, in which the dying cells unleash a ferocious inflammatory response2. A key protein involved in pyroptosis is caspase 1, and an experimental caspase-1 inhibitor made by Vertex Pharmaceuticals in Cambridge, Massachusetts, had already been tested in humans as a potential treatment for epilepsy. The drug, VX-765, failed to help epileptics, but six-week-long studies suggested that it was safe.
Greene and his colleagues tested VX-765 in HIV-infected cells cultured from human tonsils and spleens, and found that it blocked pyroptosis, prevented CD4 cell death, and suppressed inflammation. Greene hopes that the approach could one day provide an alternative or embellishment to the antiretroviral drugs currently used by 9.7 million people worldwide to manage HIV infection."
----------------------------
Cells' Fiery Suicide in HIV Provides New Treatment Hope
Most T cells are not killed by the HIV virus itself, but by the body's defense mechanism. Stopping this process could prevent a patient's progression to AIDS
http://www.scientificamerican.com
By Beth Skwarecki
The difference between HIV infection and full-blown AIDS is, in large part, the massive die-off of the immune system's CD4 T-cells. But researchers have only observed the virus killing a small portion of those cells, leading to a longstanding question: What makes the other cells disappear? New research shows that the body is killing its own cells in a little-known process. What's more, an existing, safe drug could interrupt that self-destruction, thereby offering a way to treat AIDS.
The destructive process has caught scientists by surprise. "We thought HIV infects a cell, sets up a virus production factory and then the cell dies as a consequence of being overwhelmed by virus. But there are not enough factories to explain the massive losses," says Warner Greene, director of virology and immunology at the Gladstone Institutes, whose team published two papers today in Science and Nature describing the work. (Scientific American is part of Nature Publishing Group.)
Greene suspects that researchers in the past failed to notice the process because they were looking in the wrong place. Instead of studying active CD4 T cells in the blood, his team examined spleen and tonsil tissue, where most cells are in a resting state. When HIV enters a resting cell, it transcribes its genes into DNA, but then hits a dead end: the cell's machinery isn't available to finish the replication process. This part of the story had been known for years, but Greene's team discovered that something very surprising happens next.
"Instead of that being the end of the story, cells detect that DNA in their cytoplasm and launch an immune response against it, and that immune response results in the death of those cells."
The response is a self-destruct protocol called pyroptosis. In contrast to the better-known apoptosis, in which cells die quietly without triggering inflammation, pyroptosis is "not a bland, but a fiery death," Greene says. These cells spew inflammation-causing chemicals as they die, attracting more T-cells that can then become infected themselves by the newly freed HIV. "In a bacterial infection, recruiting all these cells might be a good strategy for containing the infection," Greene says, but with HIV a vicious cycle of infection results. Pyroptosis also explains why AIDS is associated with high levels of inflammation.
Experiments by Greene's team showed that blocking a key component of pyroptosis could stop the cell death entirely; they also identified the protein that senses viral DNA to kick off the process. After studying the pathway in cultured spleen and tonsil tissue, they had an opportunity to confirm the findings in a patient's freshly removed lymph node, stained for their target proteins and viewed under the microscope. It showed the traditional virus replication happening in cells at the center of the node and resting cells dying all around. To Greene, the sight was unbelievable: "We could see this pyroptotic pathway playing out like nobody's business. In this one snapshot, we could see what we had been working on for eight years."
There's good news though: Greene estimates 95 percent of the cells that die in HIV infections are killed through pyroptosis, so the findings raise hope for a new type of treatment that could prevent HIV from progressing into AIDS. "Inhibiting activation of the immune system is not a new concept, but this gives us a new pathway to target," says Robert Gallo, director of the Institute of Human Virology at the University of Maryland School of Medicine, who was not involved in the study. He warns that other pathways may be at work that are still unknown but that this one is promising if it truly accounts for the large percentage of T cell deaths.
And in fact, a drug already exists that can block pyroptosis. Known as VX-765, it was tested years ago by Vertex Pharmaceuticals as a treatment for chronic seizure disorder. A trial showed that it wasn't effective enough against seizures, but it was safe for humans. "Now it's just sitting on a shelf waiting for a disease to cure," says Greene, who is trying to arrange a phase II trial to test the drug in HIV patients."
This is solid, interesting, useful science in the field of HIV pathogenesis," Gallo says, although he questions whether blocking the cells' death might lead them to later replicate the virus. (Greene believes the cells will degrade the viral DNA and recover.)
Greene envisions the drug, if it proves effective, as a stopgap for patients in developing countries who don't have easy access to antiretroviral drugs. It could also be an addition to such therapy. Because it targets inflammation, it could reduce the risk of aging-related diseases in patients with AIDS, who are at risk for heart attacks and kidney disease, for example, a decade earlier than noninfected peers.
--------------------
Scientists Discover How Key Immune Cells Die During HIV Infection and Identify Potential Drug to Block AIDS
Gladstone Plans to Launch Phase 2 Trial with Existing Anti-Inflammatory
http://www.ucsf.edu
December 18, 2013
Research led by scientists at the UC San Francisco-affiliated Gladstone Institutes 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.
Warner C. Greene, MD, PhD
Two separate journal articles, published simultaneously today 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 nonprofit. His lab'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 lab 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 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.
"Our studies have investigated and identified the root cause of AIDS-how CD4 T cells die," said Gladstone Staff Research Investigator Gilad Doitsh, PhD, who is the Nature paper's lead author, along with Nicole Galloway and Xin Geng, PhD. "Despite some 30 years of HIV research, this key HIV/AIDS process has remained pretty much a black box."
Once the scientists discovered this key process, as described in Nature, they began to investigate how the body senses the fragments of HIV's DNA in the first place, before alerting the enzyme caspase-1 to launch an immune response in the CD4 T cells. To identify the so-called DNA sensor, the scientists found a way to genetically manipulate CD4 T cells in spleen and tonsil 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 the paper's two lead authors.
"This identified IFI16 as the DNA sensor, which then sends signals to caspase-1 and triggers pyroptosis," says 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."
The Phase 2 trial-which will test an existing anti-inflammatory's ability to block inflammation and pyroptosis in HIV-infected people-promises to validate a variety of expected advantages to this therapy. 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 where it thwarts a cure for HIV/AIDS.
"This has been an absolutely fascinating voyage of discovery," said Greene, who is also a professor of medicine, microbiology and immunology at UCSF. "Every time we turned over an 'experimental rock' in the studies, a new surprise jumped out."
Nature article coauthors Zhiyuan Yang, PhD, Kathryn M. Monroe, PhD, Orlando Zepeda, Stefanie Sowinski, PhD, and Isa Munos Arias also participated in this research at Gladstone. The research was supported by the National Institutes of Health grants R21 AI102782, P30 AI027763 (UCSF-Gladstone Center for AIDS Research), 1DP1036502 (Avant-Garde Award for HIV/AIDS Research), U19 AI0961133 (Martin Delaney CARE Collaboratory), the A.P. Giannini Postdoctoral Research Fellowship and the UCSF/Robert John Sabo Trust Award.
Science article coauthors Jeffrey R. Johnson, PhD, Xin Geng, PhD, Gilad Doitsh, PhD, and Nevan J. Krogan, PhD, also participated in this research at Gladstone. The research was supported by the National Institutes of Health grants R21 AI102782, P50 GM082250, P01 AI090935, P50 GM081879, P30 AI027763 (UCSF-Gladstone Center for AIDS Research), 1DP1036502 (Avant-Garde Award for HIV/AIDS Research), U19 AI0961133 (Martin Delaney CARE Collaboratory); and the A.P. Giannini Postdoctoral Research Fellowship.
About the Gladstone Institutes
Gladstone is an independent and nonprofit biomedical-research organization dedicated to accelerating the pace of scientific discovery and innovation to prevent, treat and cure cardiovascular, viral, immune and neurological diseases. Gladstone is affiliated with UCSF.
--------------------------------------
How HIV Destroys Immune Cells
During HIV infection, CD4 T cells in lymphoid tissues initiate a highly inflammatory form of cell death that helps cripple the immune system.
http://www.the-scientist.com
By Dan Cossins | December 19, 2013
HIV 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."
text/pdfs attached below
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.
-----------------------------
Cell-suicide blocker holds promise as HIV therapy
Approach could complement current treatments.
Nature News
Heidi Ledford
19 December 2013
HIV infection causes a mass suicide of immune cells - a process that can be halted by an experimental drug that blocks cellular self-destruction, studies in cell cultures suggest. Researchers are now proposing a clinical trial of the drug in people with HIV.
Current HIV therapies act by targeting key proteins made by the virus. But findings from cell cultures, published today in Science1 and Nature2, suggest that targeting proteins in host cells might be an alternative approach to preserving the immune system in the face of an HIV infection.
The papers also address a decades-old mystery: why infection-fighting immune cells die off in people with HIV. A 2010 study3 showed that HIV does not directly kill most of these cells, called CD4 cells. Instead, the cells often self-destruct. "It's much more a suicide than it is a murder," says Warner Greene, a molecular virologist at the Gladstone Institute of Virology and Immunology in San Francisco, California, and a co-author of both the latest works.
Ring of fire
In the latest studies, Greene's team investigated these 'abortive' infections. They identified a sensor that detects viral DNA in the cell and activates the suicide response1. And they found that most of the cellular suicide occurs via a process called pyroptosis, in which the dying cells unleash a ferocious inflammatory response2. A key protein involved in pyroptosis is caspase 1, and an experimental caspase-1 inhibitor made by Vertex Pharmaceuticals in Cambridge, Massachusetts, had already been tested in humans as a potential treatment for epilepsy. The drug, VX-765, failed to help epileptics, but six-week-long studies suggested that it was safe.
Greene and his colleagues tested VX-765 in HIV-infected cells cultured from human tonsils and spleens, and found that it blocked pyroptosis, prevented CD4 cell death, and suppressed inflammation. Greene hopes that the approach could one day provide an alternative or embellishment to the antiretroviral drugs currently used by 9.7 million people worldwide to manage HIV infection.
Because a caspase-1 inhibitor would target a host protein rather than the virus, HIV is less likely to become resistant to the therapy, says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. But any new HIV therapy will face steep competition from the more than 30 antiretroviral drugs currently available. "You've got to be pretty good to replace the antiretrovirals," says Fauci.
Self-sacrifice
Understanding why HIV infection kills CD4 cells is an important step for researchers, says Gary Nabel, chief scientific officer at Sanofi, a pharmaceutical company headquartered in Paris. "We need to understand when a cell would rather die than let a virus infect it, and how the virus can evade that cellular suicide response to infection," he says.
But Nabel also urges caution. He worries that some of the infections that Greene and his team consider abortive may progress if the immune cells survive. "Preventing cell death is a double-edged sword in the context of HIV," he says. "Death can be protective if a T cell says 'I'm going to die before I let this virus replicate and spread to other cells.'"
Greene counters that his team looked for evidence of progression to active infection, and found none. "Pyroptosis is not a strategy to protect the host from productive infection," says Greene. "Instead, this is a pathway that actually promotes clinical progression to AIDS."
References
1. Monroe, K. M. et al. Science http://dx.doi.org/10.1126/science.1243640 (2013).
2. Doitsh, G. et al. Nature http://dx.doi.org/10.1038/nature12940 (2013).
3. Doitsh, G. et al. Cell 143, 789-801 (2010).
------------------------------
IFI16 DNA Sensor Is Required for Death of Lymphoid CD4 T Cells Abortively Infected with HIV - pdf attached
Science Dec 19 2013
Kathryn M. Monroe,1* Zhiyuan Yang,1* Jeffrey R. Johnson,1,2 Xin Geng,1 Gilad Doitsh,1 Nevan J. Krogan,1,2,3 Warner C. Greene1,2,4
1Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, CA 94158, USA. 2University of California, San Francisco, CA 94158, USA. 3QB3, California Institute for Quantitative Biosciences, San Francisco, CA 94158, USA. 4Executive Chairman, Accordia Global Health Foundation, USA.
ABSTRACT: The progressive depletion of quiescent "bystander" CD4 T cells, which are non-permissive to HIV infection, is a principal driver of the acquired immunodeficiency syndrome (AIDS). These cells undergo abortive infection characterized by the cytosolic accumulation of incomplete HIV reverse transcripts. These viral DNAs are sensed by an unidentified host sensor that triggers an innate immune response, leading to caspase-1 activation and pyroptosis. Using unbiased proteomic and targeted biochemical approaches, as well as two independent methods of lentiviral short hairpin RNA-mediated gene knockdown in primary CD4 T cells, we identify interferon-gamma-inducible protein 16 (IFI16) as a host DNA sensor required for CD4 T cell death due to abortive HIV infection. These findings provide insights into a key host pathway that plays a central role in CD4 T cell depletion during disease progression to AIDS.
These findings and a recent publication suggest that DNPK-1 may play a role in DNA sensing only within the small fraction of cells (5% in tonsil) that are permissive for productive HIV infection and trigger noninflammatory apoptosis (12). In contrast, IFI16 appears to be required to detect abortive infection and induction of highly inflammatory pyroptosis in nonpermissive CD4 T cells (Fig. 4H). These cells form the majority of HIV-1 cellular targets in most lymphoid tissues (95% in tonsil cultures). Both mechanisms likely contribute to HIV-1-induced AIDS, but at different frequencies determined by the number of permissive versus nonpermissive cellular targets residing within various lymphoid tissues.
IFI16 evolved as an anti-viral DNA sensor (2, 3). In addition, IFI16 exerts novel antiviral activity, including restriction of herpesvirus replication by inhibiting viral gene expression (29). That IFI16 is targeted for degradation by herpesviruses (30) further highlights an evolutionary pressure to counteract its activity. Our studies reveal that IFI16 initiates an innate immune response that, rather than protecting the host, drives the debilitating CD4 T cell depletion that underlies progression to AIDS in untreated HIV-infected individuals. The cycle of abortive infection, inflammatory death, and recruitment of new cells likely explains how this innate host response is undermined and, in fact, centrally contributes to HIV pathogenesis. Our findings now identify IFI16 as a critical DNA sensor required for cell death during abortive HIV-1 infection. Therapies directed against this host pathway might preserve CD4 T cells and reduce chronic inflammation--two signature pathologies in HIV infection.
----------------------------
Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection - pdf attached
Nature 19 December 2013
Gilad Doitsh1*, Nicole L. K. Galloway1*, Xin Geng1*, Zhiyuan Yang1, Kathryn M. Monroe1, Orlando Zepeda1, Peter W. Hunt2,
Hiroyu Hatano2, Stefanie Sowinski1, Isa Munoz-Arias1 & Warner C. Greene1,2,3
1Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, California 94158, USA. 2Department of Medicine, University of California, San Francisco, 505 Parnassus Avenue, San
Francisco, California 94143, USA. 3Department of Microbiology and Immunology, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, California 94143, USA
ABSTRACT: The pathway causing CD4 T-cell death in HIV-infected hosts remains poorly understood although apoptosis has been proposed as a key mechanism. We now show that caspase-3-mediated apoptosis accounts for the death of only a small fraction of CD4 T cells corresponding to those that are both activated and productively infected. The remaining over 95% of quiescent lymphoid CD4 T cells die by caspase-1-mediated pyroptosis triggered by abortive viral infection. Pyroptosis corresponds to an intensely inflammatory form of programmed cell death in which cytoplasmic contents and pro-inflammatory cytokines, including IL-1ß, are released. This death pathway thus links the two signature events in HIV infection-CD4 T-cell depletion and chronic inflammation-and creates a pathogenic vicious cycle in which dying CD4 T cells release inflammatory signals that attract more cells to die. This cycle can be broken by caspase 1 inhibitors shown to be safe in humans, raising the possibility of a new class of 'anti-AIDS' therapeutics targeting the host rather than the virus.
"Chronic inflammation might also promote maintenance of the latent HIV reservoir through the dysregulated action of the IL-7 or IL-15 cytokines stimulating homeostatic proliferation of memory CD4 T cells........The depletion of CD4 T cells and the development of chronic inflammation are signature processes in HIV pathogenesis that propel disease progression47. Our studies now reveal how pyroptosis provides an unexpected link between these two disease-promoting processes. In non-pathogenic infections in which simian immunodeficiency virus (SIV) infects its natural non-human primate hosts, caspase 3 apoptosis in productively infected cells may signal for most of the cell death rather than caspase 1, thus reducing inflammation. The pathogenic cycle of cell death and inflammation created by pyroptosis obligately requires the activation of caspase 1. As such, it may be possible to break this pathogenic cycle with safe and effective caspase 1 inhibitors. These agents could form a new and exciting 'anti-AIDS' therapy for HIV-infected subjects in which the treatment targets the host instead of the virus."
Discussion
HIV's lethal attack on its principal cellular target, the CD4 T cell, has been generally attributed to apoptosis2, 3, 4, 5, 6, 7, 8, 43. We now demonstrate that the permissivity status of the host cell dictates the pathway through which lymphoid CD4 T cells die following HIV infection. Specifically, when HIV infects permissive, activated CD4 T cells, cell death occurs silently through caspase-3-dependent apoptosis. Conversely, when either R5- or X4-tropic HIV abortively infects non-permissive, quiescent CD4 T cells from lymphoid tissue, these cells die by caspase-1-dependent pyroptosis, an intensely inflammatory form of programmed cell death. Our recent studies have identified IFI16 as the host DNA sensor that recognizes the incomplete HIV reverse transcripts thereby initiating activation of caspase 1 (ref. 44). In most human lymphoid tissues including tonsil, lymph node and spleen, the activated and permissive subset of cells represents 5% or less of the total CD4 T cells, whereas the non-permissive quiescent cells represent 95% or more of the targets encountered by HIV12, 25. Thus, in sharp contrast to previous studies2, 3, 4, 5, 6, 7, 8, 10, caspase-1-mediated pyroptosis, not caspase-3-mediated apoptosis, appears predominantly responsible for driving CD4 T-cell death following HIV infection of these lymphoid tissues. These findings are further supported by analysis of fresh lymph nodes from subjects infected with R5-tropic HIV, in which caspase 1 and IL-1ß are detected in the paracortical zone that is rich in resting CD4 T cells, whereas caspase 3 activity is detected in the anatomically distinct germinal centres where productively infected cells are found.
Our studies also highlight how lymphoid CD4 T cells are selectively primed to mount inflammatory responses as evidenced by constitutive expression of cytoplasmic pro-IL-1ß. This is particularly prominent within the CCR5-expressing subset of lymphoid CD4 T cells. The pyroptotic death of these cells would lead to high level release of IL-1ß potentially further fuelling chronic inflammation.
Pyroptosis probably promotes the rapid clearance of various bacterial infections by removing intracellular replication niches and enhancing the host's defensive responses through the release of pro-inflammatory cytokines and endogenous danger signals. However, in pathogenic chronic inflammation, such as in HIV infection, pyroptosis is not a protective response and does not lead to clearance of the primary infection. In fact, pyroptosis appears to create a pathogenic vicious cycle in which dying CD4 T cells release inflammatory signals that attract more cells into the infected lymphoid tissue to die and to produce more inflammation45 (Fig. 5c). These events establish a chronic state of inflammation that probably fuels disease progression and tissue injury46. Chronic inflammation might also promote maintenance of the latent HIV reservoir through the dysregulated action of the IL-7 or IL-15 cytokines stimulating homeostatic proliferation of memory CD4 T cells. In this regard, it will be interesting to assess to what extent pyroptosis persists in lymphoid tissues of HIV-infected subjects on effective anti-retroviral therapy.
The depletion of CD4 T cells and the development of chronic inflammation are signature processes in HIV pathogenesis that propel disease progression47. Our studies now reveal how pyroptosis provides an unexpected link between these two disease-promoting processes. In non-pathogenic infections in which simian immunodeficiency virus (SIV) infects its natural non-human primate hosts, caspase 3 apoptosis in productively infected cells may signal for most of the cell death rather than caspase 1, thus reducing inflammation. The pathogenic cycle of cell death and inflammation created by pyroptosis obligately requires the activation of caspase 1. As such, it may be possible to break this pathogenic cycle with safe and effective caspase 1 inhibitors. These agents could form a new and exciting 'anti-AIDS' therapy for HIV-infected subjects in which the treatment targets the host instead of the virus.
|
|
| |
| |
|
|
|
