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An Answer to a Longstanding Question: How HIV Infection Kills T Cells

Discussion in 'Other Health News and Research' started by guest, Nov 26, 2010.

  1. guest

    guest Guest

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    Sorry for so much bold text but I think all these parts are important.

    http://www.sciencedaily.com/releases/2010/11/101124124022.htm

    ScienceDaily (Nov. 24, 2010) Researchers appear to have an explanation for a longstanding question in HIV biology: how it is that the virus kills so many CD4 T cells, despite the fact that most of them appear to be "bystander" cells that are themselves not productively infected. That loss of CD4 T cells marks the progression from HIV infection to full-blown AIDS, explain the researchers who report their findings in studies of human tonsils and spleens in the Nov. 24 issue of Cell, a Cell Press publication.

    "In [infected] primary human tonsils and spleens, there is a profound depletion of CD4 T cells," said Warner Greene of The Gladstone institute for Virology and Immunology in San Francisco. "In tonsils, only one to five percent of those cells are directly infected, yet 99 percent of them die."
    Lymphoid tissues, including tonsils and spleen, contain the vast majority of the body's CD4 T cells and represent the major site where HIV reproduces itself. And it now appears that those dying T cells aren't bystanders exactly.
    The HIV virus apparently does invade those T cells, but the cells somehow block virus replication. It is the byproducts of that aborted infection that trigger an immune response that is ultimately responsible for killing those cells.
    More specifically, when the virus enters the CD4 T cells that will later die, it begins to copy its RNA into DNA, Greene and his colleague Gilad Doitsh explain. That process, called reverse transcription, is what normally allows a virus to hijack the machinery of its host cell and begin replicating itself. But in the majority of those cells, the new findings show that the process doesn't come to completion.
    The cells sense partial DNA transcripts as they accumulate and, in a misguided attempt to protect the body, commit a form of suicide. Greene says that completed viral transcripts in cells that are productively infected probably don't provoke the same reaction because they are so rapidly shuttled into the nucleus and integrated into the host's own DNA.
    The researchers narrowed down the precise "death window" of those so-called bystander cells by taking advantage of an array of HIV drugs that act at different points in the viral life cycle. Drugs that blocked viral entry or that prevented reverse transcription altogether stopped the CD4 T cell killing, they report. Those drugs that act later in the life cycle to prevent reverse transcription only after it has already begun did not save the cells from their death.
    Those cells don't die quietly either, Greene says. The cells produce ingredients that are the hallmarks of inflammation and break open, spilling all of their contents. That may provide a missing link between HIV and the inflammation that tends to go with it.
    "That inflammation will attract more cells leading to more infection," Greene said. "It's a vicious cycle."
    The findings also show that the CD4 T cells' demise is a response designed to be protective of the host. All that goes awry in the case of HIV and "the CD4 T cells just get blown away," compromising the immune system.

    Greene said that all the available varieties of anti-HIV drugs will still work to fight the infection by preventing the virus from spreading and reducing the viral load.
    The findings may lead to some new treatment strategies, however. For instance, it may be possible to develop drugs that would act on the cell sensor that triggers the immune response, helping to prevent the loss of CD 4 T cells. His team plans to explore the identity of that sensor in further studies. They also are interested to find out if the virus has strategies in place to try and prevent the CD4 T cells' death.
    "The cell death pathway is really not in the virus's best interest," Greene says. "It precludes the virus from replicating and the virus may have ways to repel it."
  2. lansbergen

    lansbergen Senior Member

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    Abortive HIV Infection Mediates CD4 T Cell Depletion and Inflammation in Human Lymph

    http://www.cell.com/abstract/S0092-8674(10)01245-6

    Cell, Volume 143, Issue 5, 789-801, 24 November 2010

    Abortive HIV Infection Mediates CD4 T Cell Depletion and Inflammation in Human Lymphoid Tissue

    Gilad Doitsh, Marielle Cavrois, Kara G. Lassen, Orlando Zepeda, Zhiyuan Yang, Mario L. Santiago, Andrew M. Hebbeler, Warner C. Greenesend emailSee Affiliations

    Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, CA 94158, USA Department of Medicine, University of California, San Francisco, CA 94143, USA Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA

    * Highlights
    * >95% of CD4 T cells dying after infection with HIV are not productively infected
    * Cell death involves abortive infection of nonpermissive CD4 T cells
    * The nonpermissive state leads to accumulation of abortive HIV reverse transcripts
    * These transcripts elicit suicidal innate antiviral and inflammatory responses

    Summary

    The mechanism by which CD4 T cells are depleted in HIV-infected hosts remains poorly understood. In ex vivo cultures of human tonsil tissue, CD4 T cells undergo a pronounced cytopathic response following HIV infection. Strikingly, >95% of these dying cells are not productively infected but instead correspond to bystander cells. We now show that the death of these bystander cells involves abortive HIV infection. Inhibitors blocking HIV entry or early steps of reverse transcription prevent CD4 T cell death while inhibition of later events in the viral life cycle does not. We demonstrate that the nonpermissive state exhibited by the majority of resting CD4 tonsil T cells leads to accumulation of incomplete reverse transcripts. These cytoplasmic nucleic acids activate a host defense program that elicits a coordinated proapoptotic and proinflammatory response involving caspase-3 and caspase-1 activation. While this response likely evolved to protect the host, it centrally contributes to the immunopathogenic effects of HIV.
  3. guest

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    "Greene says that completed viral transcripts in cells that are productively infected probably don't provoke the same reaction because they are so rapidly shuttled into the nucleus and integrated into the host's own DNA."

    What I don't get is why one time the virus integrates itself very fast and the other time it's so slow that the cell commits suicide.
  4. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    australia (brisbane)
    arent our natural killer cells what kill our own infected cells and cancer cells, not the cells committ suicide. Maybe nk cells work intermittenty, they get depleted, rest up, go out and fight, get depleted and repeat etc

    cheers!!!
  5. guest

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    HIV blocks a protein called Vpu to reach the cell surface. As long as Vpu does not reach the cell surface the NK cells won't kill the cell. This is why infected cells survive. However this has little to do with what is posted above because HIV depletes CD4 T cells although the cells are NOT productively infected

    "The cells sense partial DNA transcripts as they accumulate and, in a misguided attempt to protect the body, commit a form of suicide."

    "The cells produce ingredients that are the hallmarks of inflammation and break open, spilling all of their contents. That may provide a missing link between HIV and the inflammation that tends to go with it.
    "That inflammation will attract more cells leading to more infection," Greene said. "It's a vicious cycle.""

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