The HIV epidemic is a major threat to health in the developing and western worlds. A modality that targets and kills HIV-1-infected cells could have a major impact on the treatment of acute exposure and the elimination of persistent reservoirs of infected cells. The aim of this proof-of-principle study was to demonstrate the efficacy of a therapeutic strategy of targeting and eliminating HIV-1-infected cells with radiolabeled antibodies specific to viral proteins in vitro and in vivo.
Methods and Findings
Antibodies to HIV-1 envelope glycoproteins gp120 and gp41 labeled with radioisotopes bismuth 213 (213Bi) and rhenium 188 (188Re) selectively killed chronically HIV-1-infected human T cells and acutely HIV-1-infected human peripheral blood mononuclear cells (hPBMCs) in vitro. Treatment of severe combined immunodeficiency (SCID) mice harboring HIV-1-infected hPBMCs in their spleens with a 213Bi- or 188Re-labeled monoclonal antibody (mAb) to gp41 resulted in a 57% injected dose per gram uptake of radiolabeled mAb in the infected spleens and in a greater than 99% elimination of HIV-1-infected cells in a dose-dependent manner. The number of HIV-1-infected thymocytes decreased 2.5-fold in the human thymic implant grafts of SCID mice treated with the 188Re-labeled antibody to gp41 compared with those treated with the 188Re-control mAb. The treatment did not cause acute hematologic toxicity in the treated mice.
The current study demonstrates the effectiveness of HIV-targeted radioimmunotherapy and may provide a novel treatment option in combination with highly active antiretroviral therapy for the eradication of HIV.
In vitro data and results in mice suggest that HIV-targeted radioimmunotherapy is potentially safe and effective and may provide a strategy toward eradication of HIV in infected patients.
In a person infected with HIV, the symptoms of AIDS can be delayed or controlled with drug combinations such as highly active antiretroviral therapy (HAART). However, at the moment there is no cure for HIV infection or AIDS; HAART has to be taken for life and has unpleasant side effects, and the HIV virus can become resistant to some of the drugs. Even in people for whom HAART is successfully controlling disease, HIV remains at very low levels in white blood cells, and is capable of infecting more cells if treatment is stopped for some reason or becomes ineffective because the virus has developed resistance. One possible approach that could potentially eradicate HIV in an infected person is to inject antibodies, targeted against elements of the HIV particle, joined to a radioactive “tag.” The idea is that the antibodies would bind to HIV particles at the surface of infected white blood cells, and the radioactivity would then kill the infected cell. This strategy, called “radioimmunotherapy,” has been successfully used to develop treatments for certain cancers.
Why Was This Study Done?
The researchers wanted to find out whether radioimmunotherapy had any potential for treating HIV infection. As the first step, they needed to find out whether radioactive antibodies targeted against HIV proteins could kill HIV infected cells in animals, and also whether the animals suffered any serious side effects as a result. This is an early step in developing new treatments that would need to show promising results before the approach would be tried in humans.
What Did the Researchers Do and Find?
The researchers first did some experiments on HIV-infected white blood cells in vitro (i.e., test tube experiments), and second in vivo on HIV-infected PBMCs in the spleens of mice. They found that in vitro, HIV-infected white blood cells were successfully killed by radioactive antibodies that had been developed against specific proteins in the HIV particle that are routinely displayed at the surface of infected cells. Two different types of antibody, and two different types of radioactive tag, were tried. Both antibodies were very effective in targeting HIV infected cells, but one type of radioactive tag (bismuth 213) was better than the other (rhenium 188). Then, SCID mice were infected intrasplenically with HIV-infected PBMCs and treated with the radioactively tagged antibodies (these particular mice had a deficient immune system, which means that they tolerate transplanted HIV-infected human PBMCs that serve as in vivo targets for the radioactive antibodies. The number of HIV-infected human PBMCs was reduced in the treated mice compared with control animals, which were treated with antibodies not joined to a radioactive tag. The greater the antibody dose, the greater the proportion of HIV-infected human PBMC that were killed. Finally, the researchers also looked at whether the antibody treatment damaged platelets in the infected mice, and they saw a drop in platelet numbers only for the mice receiving the highest dose of antibodies.
What Do These Findings Mean?
These results provide preliminary support for the idea that radioimmunotherapy might be an approach for treatment of HIV. They argue that additional experiments in animals are warranted. If those continue to be promising, it will be critical to find out whether the radioactively labeled antibodies are safe in humans, and whether they are effective. The researchers who did this study feel that the strategy, if eventually shown to be safe and effective, would likely be of most value in preventing HIV infection very shortly after someone is exposed to the virus or treating HIV-infected patients not responsive to anti-retroviral therapy.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030427.
The Medline Plus (provided by the US National Library of Medicine) encyclopedia has an entry on HIV/AIDS
The AIDSMap provides patient information on HIV/AIDS treatment and care
The US Centers for Disease Control and Prevention has resources on HIV/AIDS treatment, including current treatment guidelines