Mechanoenzymatics of Retroviral Integration.

Retroviruses, such as the human immunodeficiency virus (HIV) occupy an important position in contemporary biomedical sciences, because many species relate to diseases or can be used as a vehicle for gene transfer. Physically speaking, HIV resembles a spherical capsule that contains minimal components. In order to successfully complete its lifecycle it critically depends on the host: as a means to hijack the cellular machinery and to establish a stable infection, the viral DNA is irreversibly introduced in the host genome. This process is called “integration”. Needless to say, this is a crucial step, and decades of research efforts have been dedicated to understand HIV integration and to materialize anti-HIV drugs. Therefore, it is somewhat surprising that the mechanism of integration at the molecular level is not yet understood. This in turn precludes a clear insight in the mode of action of anti-retroviral drugs. Our current understanding is mainly limited by the techniques that have been used thus far. In this proposal we describe new methodologies to investigate the mechanism of HIV integration using state-of-the-art, non-optical single molecule techniques. The successful project will yield a quantitative understanding of the dynamics, energetics and structural aspects of this process, and of the influences of human proteins and antiretroviral inhibitors. We believe that this unconventional biophysical approach will constitute a giant step in HIV research.