An integrated approach for HIV-cure "Shock and Kill" strategies

Short description

The development of new therapeutic approaches is still a major challenge in the treatment of HIV-1 infected patients. Part of the problem arises primarily from the virus' ability to latency: the virus hides in the genetic material of the cells and in this way becomes "invisible" to the immune system. In order to make the HI virus attackable for the immune system again, a new procedure ("shock and kill") was used in first clinical studies. Here, a stress reaction ensures that the latent viruses become active again. As a result, the immune system can then recognise and kill the cells that contain the reactivated HI virus. However, to really find and eliminate all infected cells with this method is a very complex task. For this reason, a variety of approaches are being used in this joint project to try to achieve the goal of curing the infection.

Despite years of research and the resulting improvements in HIV therapy, HIV-infected patients are dependent on taking medication for the rest of their lives. The reason for this is the special ability of the HI virus to "hide" in the DNA of the infected cell, so that it cannot be completely eliminated neither by the immune system nor by drug treatment. In this way, the virus survives indefinitely in the human body, and the infection can be reactivated at any time after HIV therapy is discontinued.

In this project, a novel therapy procedure for HIV infections is being developed, called "shock and kill" therapy. In particular, it is being investigated whether this therapy approach will make it possible in future to completely remove the HI virus from the human body after an infection, and thus completely cure an HIV infection.

To achieve this goal, we are investigating the exact structures that appear on the surface of infected cells after a stress stimulus ("shock") and through which the immune system can recognise and kill an infected cell. Since the immune system has several arms of defence against infection, we are specifically looking for different points of attack that are specific to the different arms of the immune system.

We are also investigating which structural changes the HI virus uses to develop strategies to escape the immune system. We assume here that some viral structures have a higher flexibility and change more quickly, while other structures do not change so quickly or not at all, as this would be associated with a disadvantage for the virus. Consequently, the latter structures represent a better target for therapeutic measures.

Another focus is on intensive research into the prevention of so-called autophagy triggered by the virus. Autophagy is the process in cells by which they break down and utilise their own components. The inhibition of autophagy occurs through the manipulation of various intracellular signalling pathways by HIV and represents another ability of the virus to protect itself from cellular defence mechanisms. Which signalling molecules are specifically affected, what influence they have in the infection process and which pharmacological options are available to intervene in this process are being extensively evaluated in this project.