Radiolabeled antibodies kill HIV-infected cells in preclinical studies

Cancer has long been the target of radioimmunotherapy, which uses radioactive isotopes piggy-backed to antibodies or their fragments. Now HIV may have come into the modality's sights as well. If all works according to plan, molecular imaging could play a key role in the development of this therapy and its application.

Researchers at Albert Einstein College of Medicine in Bronx, NY, have demonstrated a novel approach in mice that uses radioactively tagged vehicles to target and destroy cells infected with human immunodeficiency virus. Two types of antibodies and two types of radioactive tags were tried in preclinical studies. All were effective in targeting HIV-infected cells. Both radioisotopes are easily imaged using gamma cameras.

"My whole point in using those isotopes is to make imaging possible because it is very important," said Dr. Ekaterina Dadachova, an associate professor of nuclear medicine and microbiology and immunology at Albert Einstein. Dadachova's work is published in the November issue of Public Library of Science Medicine. "You can give a small dose to image and give a large dose for therapy and to image also."

Molecular imaging will be a critical part of clinical research now being planned and in the eventual use of this therapy, if it gets into the clinical mainstream, Dadachova said.

Imaging will be used to determine the burden of HIV cells in a patient and to gauge the effect of treatment, she said. Imaging could prove particularly important in late-stage patients, she said. HIV cells hiding in the lymph nodes and spleen, for example, must first be activated by certain compounds that cause these cells to express the antigen targeted by the radiolabeled antibodies.

"You have to make sure that you activate those cells - that they are not dormant anymore," she said. "I cannot imagine any treatment with radiolabeled antibody or other carriers without prior imaging. So imaging will be an inherent part of this."

Today radioimmunotherapy is an accepted treatment for several types of cancer, including non-Hodgkins lymphoma. Since 2001, Dadachova has pioneered its use against infectious diseases. Her team has successfully used radioimmunotherapy first against the major fungal pathogen Cryptococcus neoformans, which can cause life-threatening encephalitis in AIDS patients and other people with weakened immune systems; then applied to streptococcal bacterium responsible for pneumonia; and, most recently, in HIV.

Unlike the earlier work, which targeted fungi and bacteria directly, in the case of HIV, Dadachova aimed for the immune cells that the virus infects. Potentially this approach could be used against many viral infections, from the hepatitis C virus to the Ebola virus, in which viral proteins are expressed on the surface of infected cells.

In the HIV research, the target was protein gp41, one of several proteins in the HIV-1 virus displayed on the surface of infected cells. After obtaining antibodies that would latch specifically onto gp41, the researchers tagged them with two different radioisotopes, 213-bismuth and 188-rhenium.

To test the therapy, the researchers first injected HIV-1-infected human white blood cells into the spleens of immune-deficient mice. 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 mouse spleens, and found the number significantly reduced compared to those of control subjects.

Further testing revealed that 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, but we currently have no way of eliminating the HIV-infected cells that make these infections chronic," said Dr. Harris Goldstein, director of the Center for AIDS Research at Albert Einstein Medical College. "If we could eradicate all the HIV-infected cells in a patient, which would likely require a combination of therapies, then we could start to think about curing HIV-infected patients."