A modified version of cancer therapy that uses radioactive molecules to seek out and destroy malignant cells has proven effective in killing HIV-infected cells in mice, according scientists in the U.S. and Germany (PLoS Med 2006, 3(11): e427; http://dx.doi.org/10.1371/journal.pmed.0030427). If the preliminary findings hold true in humans, radioimmunotherapy (RIT) might eventually be used to prevent HIV infection just after a person is exposed to the virus or to treat HIV-infected patients who fail to respond to antiretroviral therapy. “And the good thing is that it would work even on multidrug resistant HIV,” says lead author Ekaterina Dadachova of the Albert Einstein College of Medicine in New York.
In recent years, RIT has been successful in treating non-Hodgkin lymphoma. In that application, monoclonal antibodies carrying isotopes of yttrium and iodine target cancerous cells, ‘zapping’ them with a lethal dose of radioactivity. Dadachova and Arturo Casadevall have been developing RIT for treatment of fungal and bacterial infections since 2001. To see how well the method might fight HIV infection, they teamed up with AIDS researchers Harris Goldstein from the Albert Einstein College of Medicine and Susan Zolla-Pazner from New York University. The researchers tagged antibodies to the HIV-1 envelope glycoproteins gp120 and gp41with either the radioisotope bismuth 213 (213Bi) or the radioisotope rhenium 188 (188Re), isotopes that have previously been used in preclinical and clinical studies.
Using chronically HIV-1-infected T cells and acutely HIV-1-infected human peripheral blood mononuclear cells (hPBMC), the researchers showed that both antibodies to gp120 and gp41 selectively delivered their deadly payloads in vitro. However, 213Bi proved more lethal.
The scientists followed up with in vivo treatments on immunodeficient (SCID) mice. In one set of experiments, mice harboring HIV-1-infected hPBMC in their spleens were injected with a 213Bi- or 188Re-labeled monoclonal antibody to gp41. Depending on the dose, more than 99% of HIV-1-infected cells were eliminated. A second set of tests on SCID mice with implants of human thymic and liver tissue showed a 2.5-fold reduction in the number of HIV-1-infected cells in the implants of mice that had received a 188Re-labeled antibody to gp41 compared with those treated with a 188Re-tagged monoclonal antibody control.
In addition, the RIT did not appear to damage non-HIV-infected blood cells. Only mice that received the highest amount– 160 μCi (5.92 MBq) or twice the therapeutic dose – of the 188Re-labeled antibody to gp41 suffered a drop in platelet numbers. The “slight nonsignificant” loss of platelets occurred 7 days after RIT, and the counts returned to normal a week later. The lack of peripheral damage “likely reflects the very specific targeting of HIV-1-infected hPBMC by the radiolabeled monoclonal antibody,” the scientists note.
Radioimmunotherapy to treat HIV infection would likely take a multistep approach. First, antiretroviral therapy would be administered to significantly decrease the viral load. Then an agent, such as valproic acid, would be used to ‘wake up’ dormant HIV-infected cells hiding in the body. Finally, treatment with RIT would rout out those newly activated infected cells.
The researchers have teamed with an industrial partner to continue the preclinical work, including development of a method to reliably produce the isotope-tagged antibodies on a large scale. If all goes well, clinical trials to test RIT for treating HIV infection in humans could begin within two years, Dadachova says.