Dr. Silke Hoffmann (left) and Dr. Alexandra Boeske investigated how the HIV protein NEF is transported.
Around 37 million people around the globe are living with HIV. Acquired immunodeficiency syndrome (AIDS) is still not curable and the virus poses countless questions for researchers. A working group headed by Dr. Silke Hoffmann has solved one such question – and gained astounding insights.
For a long time, the NEF protein – one of the 18 proteins which HIV consists of – was viewed as unimportant in the development of the disease. “This is attested by its name: NEF is short for negative factor,” explains Silke Hoffmann from Jülich’s Institute of Complex Systems (ICS-6). Science has long since corrected its insights and learned that NEF manipulates the human immune system in a multitude of ways. It contributes to HIV spreading within the body and causing damage.
Image above: Dr. Silke Hoffmann (left) and Dr. Alexandra Boeske investigated how the HIV protein NEF is transported.
Just how important NEF is in the development of the illness is reflected in people infected with the virus: the structures of over 200 amino acid residues are defective. “These people can carry HIV for very long periods of time without the illness actually breaking out,” says Hoffmann. For this reason, there is great scientific interest in decoding the various functions of NEF. The Jülich researchers have contributed important insights in this respect, particularly Hoffmann’s former postdoc Dr. Alexandra Boeske. Even at school, she was already interested in studying AIDS: “During a senior year at school, I worked intensively on the illness and the virus that causes it, as well as on NEF,” the 31-year-old recalls.
Boeske’s research results and observations concerning the protein have attracted a lot of attention, particularly the link between NEF and the autophagy process. This mechanism recycles “waste” such as broken molecules and cell organelles – and also disposes of foreign objects such as viruses and bacteria. The cell biologist was therefore invited to attend conferences and symposia all over the globe. Her promising results also formed the basis of a project which was launched in 2015 by the German Research Foundation (DFG) and is part of the collaborative research centre of Heinrich Heine University Düsseldorf. “Thanks to this project as well as further funding, Alexandra Boeske’s former ‘one-woman show’ has now become a research group of five doctoral researchers investigating autophagy and NEF,” says a delighted Silke Hoffmann.
The Jülich team recently published its latest results. The virus needs to reach the cell membrane in order to carry out some of the functions that end up weakening the immune system. How it gets there, however, is not yet understood. The Jülich scientists have now shown that NEF requires a sort of taxi for transportation, the GABARAP protein. When the researchers switch off this protein taxi, NEF no longer reaches its destination. This is a decisive finding – especially since the docking of NEF to the cell membrane is so important for many effects concerning the development of the illness. Fittingly, the researchers also observed that NEF transportation from the cell is inhibited if GABARAP is missing. The team now want to investigate what happens in HIV-infected cells in which GABARAP is missing together with virologists from Erlangen and Düsseldorf . The most exciting question will be whether the processes causing the externally visible weakening of the immune system still occur.
proteins make up HIV. NEF is one of them.
GABARAP is a member of a protein family involved in transport processes inside cells as well as their autophagy – the very reason why Silke Hoffmann and her team are now concerned with this process. “Some pathogens have learned how to escape autophagy or even make use of it for themselves – just like HIV. We believe that it ‘hijacks’ parts of the autophagy system in order to be transported out of an already infected cell and trigger a sort of self-destruct programme in healthy neighbouring cells,” explains the group leader.
In order to verify this theory, the researchers intend to investigate NEF and GABARAP in detail, or more accurately: tiny bubbles in the cell which wrap around the proteins during transport. These “vesicles” usually have a simple membrane as their outer shell, whereas autophagic vesicles possess a double membrane. “If we can use electron-microscopic images to show that NEF and its taxi GABARAP are transported by such double-membrane vesicles, this would prove that autophagy plays an important role in releasing NEF,” explains Hoffmann. The structural and molecular biologists are planning to present the precise relation between autophagy, GABARAP, and NEF in another publication. In the distant future, blocking the GABARAP–NEF interaction could permit the development of a therapeutic approach. “But that is still a long way off. We are conducting basic research,” emphasizes the Jülich researcher.
Images: Forschungszentrum Jülich/Wilhelm-Peter Schneider, Jens Neubert, Sentavio/Shutterstock