Infection of activated T cells: A novel targetable pathway

HIV-1-induced nuclear invaginations mediated by VAP-A, ORP3, and Rab7 complex explain infection of activated T cells: A novel targetable pathway

Authors

Mark F. Santos, Germana Rappa, Jana Karbanová, Patrizia Diana, Girolamo Cirrincione, Daniela Carbone, David Manna, Feryal Aalam, David Wang, Cheryl Vanier, Denis Corbeil, and Aurelio Lorico

What is the research?

The nucleus is the center of command for the cell. It contains DNA, that is protected by a special membrane that keeps unwanted visitors from entering the nucleus. Most viruses need access to the nucleus to make new copies of themselves so they can go on to invade other cells. But no one clearly understands how viruses get past the protective membrane of the nucleus. Our study has found the HIV, the virus that causes AIDS, can enter the cell wrapped inside a membrane package that comes from the infected cell. These packages are called endosomes, and they can contain not only viruses, but many other things the cell may or may not need. The endosome-wrapped virus then travels to the outside of the nuclear membrane and pushes it inward to form what we call ‘nuclear invaginations.’

The virus-containing endosome then moves inside the nuclear invagination to its tip, where the virus enters the nucleus. In trying to understand how this process occurs, we have discovered a complex of three proteins which are required for the formation of the invaginations and the movement of HIV-containing endosomes to the tip of the nuclear invagination, and for entry of the virus into the nucleus. One protein is located on the membrane packaging of the endosome, the second one is on the nuclear membrane where the invagination occurs, and the third protein connects the first two proteins together.  We used molecular modeling to synthesize a molecule, a potential drug, that blocks the protein complex from forming by attaching to the protein responsible for connecting the other two together. When we infected T cells with HIV in the presence of our potential drug, the virus was not able to enter the nucleus and infection was prevented.

What is the impact of the research?

We really don’t know how the hundreds of thousands of types of proteins all interact inside human cells. This makes it very difficult to identify the few proteins critical for understanding how healthy cells work and what goes wrong in a diseased cell. Scientifically, we have revealed a protein pathway that appears to have a direct impact on diseases. This is good for two reasons. First, this means our team and others can work to understand how this pathway and its proteins are involved in all kinds of disease, not just viral diseases. In fact, one of the most interesting facts about this viral research is that we study cancer. We first found this pathway while trying to understand how seemingly healthy cells can allow spread of cancer to other areas of the body (metastasis). It appears this pathway may impact that process. We are also looking at other diseases like Alzheimer’s which have as a component the entry of bad substances into the nucleus. The second good thing about having a new pathway to target is that it opens up a new area for potential drug development. 

What are the translational benefits of the research?

This is an entirely new pathway and we have developed molecules (drugs) that block it. Although our research is at a pre-clinical stage, it is likely that the new drugs synthesized may have therapeutic activity in AIDS, other viral diseases and possibly metastatic cancer and other diseases where nuclear transport is involved. SARS-Cov2, the virus that causes COVID-19, does not require nuclear entry to infect cells, so this pathway wouldn’t be an important drug target. However, there are many viruses that require nuclear entry, and the next pandemic may be caused by one of those. Finding new protein pathways which can be targeted for drugs helps build an strong arsenal against future pandemics.

What is the future of the research and its benefits to humanity?

Because the pathway we found may apply to many types of diseases, there is a tremendous amount of work that needs to be done to understand the full benefits this research may have for humanity. For example, Dr. Arena at McGill University found that packets released by cancer cells can enter into endosomes of normal cells in distant organs like lung or liver and reach their nuclei through the invaginations, transforming them into cells that behave as cancer metastatic cells. Therefore, our drugs, that block the nuclear transport, may block some types of cancer metastasis, the main cause of cancer death. However, it is always a challenge to interrupt a disease without also interrupting things that healthy cells are doing (for example, side effects such as hair loss and vomiting with chemotherapy). At this stage, we all proceed with enthusiastic caution to understand the biology of the protein nuclear pathway as much as possible and try to target potential drugs in a way that will help alleviate disease burdens on patients of the future without causing harm. 

Contact Us