T cells are types of white blood cells that help to protect our bodies from infection. In a person who is HIV positive, the virus attacks these blood cells and weakens the body’s ability to fight off infections, viruses and bacteria. Part of what makes HIV so difficult to cure is that is a retrovirus – meaning that it replicates by inserting a DNA copy of itself into the T cell. Scientists hypothesise that we can attack the virus on two fronts by genetic reengineering of cells. The first front reengineers the T cells to be protected from the virus (defensive arm). The second front additionally reengineers the T cells to attack any cell infected with HIV (offensive arm).
The challenge is that the T cells that HIV attacks are very difficult to deliver genes to. We are currently only able to deliver genes to T cells that are activated, and even once they are activated the process of genetic manipulation is not efficient. Based on decades of research, we have developed a series of new generation viral gene therapy vectors that are highly efficient and we are able to deliver genetic material to resting T cells in the lab. This unique approach has immense potential in engineering T cells to be used in HIV cure efforts (as well as in cancer immunotherapy).
At present, there is no scalable and efficient viral based system of gene delivery of resting T cells. This project aims to harvest and tune the key aspects of genetically modifying resting cells in our immune system.
Viral based gene therapy vectors are limited in entering resting cells at two key levels:
- Crossing the plasma membrane
- Converting genetic cargo from RNA to DNA.
In this project, we engineer viral particles from the inside out using the same key components that HIV and the related virus have successfully used to enter resting cells of our immune system. We will then assess the ability of these newly formed viral particles to initially fuse with target cells and secondly to determine if they can genetically modify them. Once this is achieved, we will look at ways to optimise the process.
We have successfully genetically modified myeloid cells to enable protection against HIV and have turned our attention to the same goal in resting T cells. We can now genetically modify significant proportions of resting T cells without the need to stimulate them through activation or through cytokine stimulation.
This research has the potential to bring us closer to a functional HIV cure by:
- Determining a way to effectively deliver genes to resting T cells.
- Optimising the process of gene delivery by engineering the virus to do the work of genetic delivery.