Radioimmunotherapy clears HIV-infected cells in mice

Attaching radioactive particles to antibodies that target HIV envelope proteins resulted in clearance of more than 99% of HIV-infected cells from the spleens of immunodeficient mice, researchers from the US and Germany report in an article released this week by PloS Medicine. Radioimmunotherapy may have the potential to eradicate hard-to-clear HIV-infected cells from the body without serious toxicity, the researchers suggest.

Radioimmunotherapy using monoclonal antibodies tagged with isotopes is already used successfully in cancer therapy to eliminate cancerous cells in B-cell non-Hodgkin lymphoma, and has been demonstrated to clear bacterial and fungal infections in proof-of-concept experiments. Radioimmunotherapy may soon be approved as a first-line therapy for some forms of lymphoma.

In HIV infection chronicly infected cells form a reservoir of HIV infection that has proved impossible to eliminate even after long periods of viral suppression using antiretroviral therapy, and scientists have begun to look at other methods of clearing the viral reservoir in the hope that the infection can eventually be eradicated from the body. Chronicly infected cells may also harbour drug-resistant viruses that can provide a reservoir to fuel viral rebound in treatment-experienced patients

This study used monoclonal antibodies to HIV’s gp120 and gp41 envelope proteins, tagged with bismuth 213 and rhenium 188 respectively, and tested their relative effectiveness at eliminating HIV-infected white blood cells in the test tube. The white blood cells infected by HIV, lymphocytes, are amongst the cells most sensitive to radiation in the human body, so even a very small dose delivered directly to a lymphocyte is enough to kill it.

The test tube study found that bismuth-linked antibodies were more effective, and that an antibody to the gp41 protein designed to bind to the 246-D region ( a conserved sequence present across a wide range of genetically diverse HIV strains) was highly effective. Importantly, none of the antibodies killed cells in samples that did not contain HIV-infected cells.

Immunodeficient mice that had been infected with HIV were treated with a single dose of the radiolabelled antibody, resulting in a significant reduction in HIV-infected cells of greater than 99%.

Further mouse studies using a thy/liv SCID-hu mouse, engineered to develop thymus tissue that can produce CD4 cells, sought to determine whether infection of thymic tissue could be blocked by radiolabelled antibodies. Treatment with the rhenium-associated gp41 antibody reduced the number of HIV-infected thymoctes by more than 95% when compared to a control treatment lacking a gp41 antibody.

The study also found little or no haematologic toxicity, unlike that seen with radiolabelled antibodies targeting cancerous cells. The authors of the study say this lack of toxicity probably reflects the fact that clearing virally infected cells through targeting of viral proteins displayed on the cell surface allows radioisotopes to be targeted much more specifically, and with much less potential for damage to other host cells.

The authors note that any radioimmunotherapy approach using monoclonal antibodies must be able to out-compete human antibodies against HIV, either by using very high doses of antibodies or by very specific targeting of HIV epitopes by antibodies. They also remark that the approach may be able to clear quiescent HIV-infected cells that have already been stimulated by valproic acid, an agent which has been shown to activate them.