November 6, 2006 (Bronx, NY) Using a radically new strategy featuring radioactive "guided missiles," researchers at the Albert Einstein College of Medicine of Yeshiva University have successfully targeted and destroyed human immune cells infected with HIV, the virus that causes AIDS.
"This study in mice supports the idea that radioimmunotherapy might help in treating people infected with HIV," says Dr. Arturo Casadevall, chair of the department of microbiology and immunology at Einstein and a senior author of the study, which appears in the November issue of PLoS Medicine. "More broadly, this work introduces a new approach for treating the many viral infections, from hepatitis C to Ebola, in which viral proteins are expressed on the surface of infected cells."
The Einstein researchers used a technique called radioimmunotherapy, in which radioisotopes are piggy-backed onto antibodies. Once these precision-made molecules are injected into the body, the antibodies home in on a specific protein target…and the radioisotope "warhead" destroys the cell to which that protein is attached.
Radioimmunotherapy is an accepted treatment for several types of cancer including non-Hodgkins lymphoma. But only at Einstein has it been tried against infectious diseasesan idea pioneered by Dr. Ekaterina Dadachova, the study's lead author and an associate professor in the departments of nuclear medicine and microbiology & immunology.
In a series of animal studies beginning in 2001, Dr. Dadachova and her colleagues have successfully used radioimmunotherapy against a variety of disease-causing microbesfirst the major fungal pathogen Cryptocccus neoformans, which can cause life-threatening encephalitis in AIDS patients and other people with weakened immune systems; then a streptococcal bacterium responsible for pneumonia; and now HIV. The researchers zapped the fungi and bacteria directly, but, in the case of HIV, they aimed for the immune cells that the virus infects.
In this study their target was the protein gp41, one of several proteins in the HIV-1 virus that are "displayed" on the surface of HIV-1-infected cells. After obtaining antibodies that would latch specifically onto gp41, the researchers tagged them with two different radioisotopes, bismuth 213 and rhenium 188.
To test the therapy, the researchers first injected HIV-1-infected human white blood cells into the spleens of immune-deficient mice. (The spleen was chosen because the overwhelming majority of HIV-1-infected cells in humans are present in the spleen and other lymphoid tissues; and the absence of an immune system meant the mice could not mount an immune attack against the "foreign" human white blood cells.) One hour later, the mice were injected with the radioactive antibodies.
Three days after treatment, the researchers measured the number of HIV-1-infected cells in the spleens of the mice. Compared with control mice (which were treated with antibodies not attached to radioisotopes), the number of HIV-1-infected human white blood cells in the treated mice was significantly reduced. The greater the antibody-radiosotope dose, the greater the proportion of HIV-1-infected cells that were killed. Both isotopes proved effective in eliminating the virus-infected cells from the mice, which experienced no significant adverse effects from the treatment.
"Today's antiretroviral drug therapies can inhibit the multiplication of HIV and help prevent HIV from infecting additional cells," says Dr. Harris Goldstein, Director of the Center for AIDS Research at Einstein. "But we currently have no way of eliminating the HIV-infected cells that make these infections chronic. The novelty of this technique is that it targets the cells infected by HIV, which act as 'factories' for making more of the virus. So if we could eradicate all the HIV-infected cells in a patientwhich would likely require a combination of therapies--then we could start to think about curing HIV-infected patients."
Dr. Goldstein, also a senior author of the study, notes that radioimmunotherapy might be particularly useful for people newly exposed to HIV, such as healthcare workers with needlestick injuries. "Studies show that giving highly active antiretroviral therapy (HAART) to people within 24 hours of exposure to HIV can prevent infection from developing," he says. "But if several days have passed, the virus is able to infect enough cells to cause a chronic HIV infection. By combining HAART with radioimmunotherapy, we may be able to prevent lifelong infection in these people by eliminating those initially infected cells."
Clinical trials using radioimmunotherapy for treating HIV infection are now being planned.
The research was funded by the Lehman Brothers Foundation, the National Institutes of Health and the NIH-funded Einstein/MMC Center for AIDS Research.
The study's other Einstein authors were Drs. Mahesh C. Patel and Sima Toussi. The antibody against gp41 was provided by Drs. Miroslaw K. Gorny and Susan Zolla-Pazner of the New York University School of Medicine. Dr. Martin W. Brechbiel of the National Cancer Institute and Drs. Christos Apostolidis and Alfred Morgenstern of the Institute for Transuranium Elements in Karlsruhe, Germany, also collaborated.
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