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New Scientist
21 May 2010 by Linda Geddes, Baltimore
http://www.newscientist.com/article/mg20627614.600-remove-hivs-invisibility-cloak-to-defeat-it.html
REMOVING a chemical "invisibility cloak" that makes HIV-infected cells look healthy might be the key to ridding people of the virus.
Human cells protect themselves against immune attack by displaying proteins on their surface that mark them as "self". When the immune system detects these proteins, it holds back. One way HIV evades immune attack is by hijacking one of these proteins - CD59 - and using it to disguise itself and the cells it infects as healthy, human cells.
This cloak doesn't kick in directly following HIV infection. First, antigens on HIV's surface prompt the immune system to pump out vast quantities of anti-HIV antibodies, which bind to the antigen and even trigger the destruction of some HIV. But once the infection is established, the CD59 cloak prevents further immune attack on the viral particles and infected cells, which also display the antigen (see diagram, right). "HIV patients have a very strong antibody response, but unfortunately it doesn't work," says Qigui Yu of the Indiana University School of Medicine in Indianapolis.
To kick-start this immune attack, Yu and Xuebin Qin of Harvard Medical School wanted to find a way to remove this cloak. They knew that a bacterium found in the human throat secretes a toxin called intermedilysin that binds to CD59. By isolating the toxin's binding site they made a small molecule called rILYd4.
When they added this molecule to blood from people with HIV, it enabled the antibodies already in the blood to destroy viral particles. Red blood cells and uninfected immune cells were unscathed, probably because there were no antibodies specific to these cells present (The Journal of Immunology, DOI: 10.4049/jimmunol.0902278).
Yu has preliminary results suggesting rILYd4 fights infected cells too. At the American Association of Immunologists' meeting in Baltimore, Maryland, last week, he reported that his team infected human immune cells with HIV and exposed them to rILYd4 plus antibodies taken from people with HIV. This destroyed some infected cells, he says, as did transferring another set of HIV-infected human cells to mice subsequently injected with rILYd4 and anti-HIV antibodies.
Robert Siliciano, who researches HIV at Johns Hopkins University in Baltimore, says the approach is interesting. However, he cautions that it may not work against infected cells that have entered a resting state, in which they no longer express HIV antigens.
Yu's answer is to use a "shock and kill" strategy. This involves reactivating infected cells so they express HIV antigens, before adding rILYd4. Meanwhile, Qin's team is trying to reduce the chances of rILYd4 blocking CD59 in normal cells as well as HIV-infected ones, preventing an immune attack on healthy cells.
The drug could prove useful as antiretroviral drugs don't clear the body of HIV. "If you stop using the drug, the virus can bounce back very quickly," Yu says
21 May 2010 by Linda Geddes, Baltimore
http://www.newscientist.com/article/mg20627614.600-remove-hivs-invisibility-cloak-to-defeat-it.html
REMOVING a chemical "invisibility cloak" that makes HIV-infected cells look healthy might be the key to ridding people of the virus.
Human cells protect themselves against immune attack by displaying proteins on their surface that mark them as "self". When the immune system detects these proteins, it holds back. One way HIV evades immune attack is by hijacking one of these proteins - CD59 - and using it to disguise itself and the cells it infects as healthy, human cells.
This cloak doesn't kick in directly following HIV infection. First, antigens on HIV's surface prompt the immune system to pump out vast quantities of anti-HIV antibodies, which bind to the antigen and even trigger the destruction of some HIV. But once the infection is established, the CD59 cloak prevents further immune attack on the viral particles and infected cells, which also display the antigen (see diagram, right). "HIV patients have a very strong antibody response, but unfortunately it doesn't work," says Qigui Yu of the Indiana University School of Medicine in Indianapolis.
To kick-start this immune attack, Yu and Xuebin Qin of Harvard Medical School wanted to find a way to remove this cloak. They knew that a bacterium found in the human throat secretes a toxin called intermedilysin that binds to CD59. By isolating the toxin's binding site they made a small molecule called rILYd4.
When they added this molecule to blood from people with HIV, it enabled the antibodies already in the blood to destroy viral particles. Red blood cells and uninfected immune cells were unscathed, probably because there were no antibodies specific to these cells present (The Journal of Immunology, DOI: 10.4049/jimmunol.0902278).
Yu has preliminary results suggesting rILYd4 fights infected cells too. At the American Association of Immunologists' meeting in Baltimore, Maryland, last week, he reported that his team infected human immune cells with HIV and exposed them to rILYd4 plus antibodies taken from people with HIV. This destroyed some infected cells, he says, as did transferring another set of HIV-infected human cells to mice subsequently injected with rILYd4 and anti-HIV antibodies.
Robert Siliciano, who researches HIV at Johns Hopkins University in Baltimore, says the approach is interesting. However, he cautions that it may not work against infected cells that have entered a resting state, in which they no longer express HIV antigens.
Yu's answer is to use a "shock and kill" strategy. This involves reactivating infected cells so they express HIV antigens, before adding rILYd4. Meanwhile, Qin's team is trying to reduce the chances of rILYd4 blocking CD59 in normal cells as well as HIV-infected ones, preventing an immune attack on healthy cells.
The drug could prove useful as antiretroviral drugs don't clear the body of HIV. "If you stop using the drug, the virus can bounce back very quickly," Yu says