Nanobody activates immune response to kill HIV-infected cells

Disease and treatment 11. apr 2023 2 min Professor Martin Tolstrup Written by Kristian Sjøgren

Researchers have developed a technology that binds HIV-infected cells to the complement system, part of the innate immune system that targets the HIV-1 envelope protein and then kills the infected cells. A researcher say that people can live their whole lives with HIV, but this may be a definite cure.

Today, people can live with HIV if they take medicine that keeps the viral load down.

However, there may be hope for a future in which HIV can not only be contained but can also be completely cured.

To realise this, researchers have developed a method to bind antibodies on the surface of HIV-infected cells to the complement system. The immune system then kills the HIV-infected cells without harming the uninfected cells.

According to a researcher behind the development of the method, the results are a first step towards a new way of treating not only people living with HIV but also people with other diseases.

“We achieved the desired result, and this proves that we can use this technology to kill HIV-infected cells. Based on the result, my collaborators have established a company to investigate whether this therapeutic approach can also be used to treat people with cancer,” explains Martin Tolstrup, Professor, Department of Clinical Medicine, Aarhus University.

The research has been published in EMBO Molecular Medicine.

Binds the immune response and HIV-infected cells together

The researchers killed HIV-infected cells in two ways.

Martin Tolstrup is an expert in developing antibodies that can recognise antigens on the surface of cells, and he has worked with antibodies that very specifically identify and bind to specific cells that are infected with HIV.

However, the problem has been that researchers have not been able to develop a method to induce the cells of the immune response to actively kill the HIV cells – even after antibodies have been attached to their surface.

The second part of the technology the researchers have developed relates to the complement system, which does not comprise immune cells but instead comprises proteins that circulate in all body fluids.

When these specialised proteins encounter a threat, such as a bacterium, they join together and form a pore through the surface membrane of the threat, killing it.

“In connection with my research, I contacted some colleagues who had developed a technology called a nanobody that can recruit the complement system quite effectively. Then we put their nanobody together with my antibodies to recognise HIV cells to determine whether we could get the whole complex to recognise and kill HIV-infected cells,” says Martin Tolstrup.

Effectively kills HIV-infected cells

In the studies of the combined molecule, the researchers found that they had created a highly selective system to kill HIV-infected cells.

The researchers conducted studies to determine whether the developed nanobody could induce the complement system to HIV-infected cells – and it did.

The researchers then carried out experiments in which they mixed HIV-infected cells with healthy cells and the nanobody they had developed, and once again they saw that the system only attacked the HIV-infected cells and left the healthy cells alone.

Finally, the researchers tested their system on mice and saw that the nanobody system is concentrated in the lymph nodes of the mice, where it can exert its effect.

“We achieved the results we had hoped for and need in order to move forward to develop the system. Based on the positive results, my colleagues have established a company that will drive this further development,” explains Martin Tolstrup.

Curing cancer?

However, the further development of the nanobody system did not initially focus on curing people living with HIV but instead on people with cancer.

Just as the complement system can be induced to attack HIV-infected cells, the researchers hope that they can also induce it to attack cancer cells by binding with antibodies to antigens on the surface of the cancer cells in the same way.

The potential in developing a new type of drug for treating people with cancer has led investors to become involved in the project.

“Our proof-of-concept study shows that the system works against HIV. My colleagues are now fully focused on demonstrating its potential for treating people with cancer. If they are successful in developing drugs in that direction, we may return to HIV and determine whether there are also opportunities to develop a definite cure for HIV, so that people living with HIV do not have to undergo lifelong treatment with drugs but can be completely cured,” concludes Martin Tolstrup.

Nanobody-mediated complement activation to kill HIV-infected cells” has been published in EMBO Molecular Medicine. The project has been supported by Independent Research Fund Denmark and by the Novo Nordisk Foundation through a 2019 Research Leader Programme grant to Martin Tolstrup.

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