Characterization of HIV-human complexes: focus on Vpu

Stefanie Jaeger
University of California, San Francisco
Basic Biomedical Sciences

Human Immunodeficiency Virus 1(HIV-1) attacks the immune system of humans thereby causing the worldwide pandemic AIDS. An HIV particle is fundamentally a spherical shell made of fat and proteins, enclosing a construction plan for producing more virus particles. Like all viruses, HIV cannot grow or reproduce on its own; in order to make new copies of itself it must enter the cells of a human. Since the virus particle is very small, about a million times smaller than the average cell humans and animals are made of, it can only package very little information, namely exactly nine plans (genes). For comparison, a human cell contains over 20,000 of such genes. In order to realize these blueprints, i.e. to produce new viral components, deliver them to the right place, assemble them and set free a new particles from the cell that can infect new cells, different machineries are needed. Since the virus itself does not have these machines, it uses the ones from its host, the human white blood cell. To do so, viral proteins often mimick parts of cellular machineries so that the cell incorporates the viral protein instead of its own protein. That way the virus hijacks the cellular machinery for its own purpose and misuses it to make new viruses instead of proteins the cell needs. The cell, however, has developed counterstrategies to fight the virus. One of these strategies was discovered only recently: a tether on the surface of the host cell captures newly made viruses so that they cannot escape from the cell. The virus in turn has also developed a countermeasure to defend itself against this tether: one of its nine construction plans contains the information for making a small protein called Vpu, which removes the tether from the cell surface so that the virus can escape.

Since every step of the virus replication relies on interactions of viral and human proteins, it is essential for us to identify these interactions so that we can develop drugs to block them. My research proposal therefore aims at identifying HIV-human protein assemblies in a comprehensive and systematic manner by ‘fishing’ each of the HIV proteins out of human blood cells and identify the human protein that bound to it. Since there are always proteins that unspecifically stick to a bait, comparing the different HIV proteins helps to sort out these impurities. I am especially interested in proteins bound by the Vpu protein because it can help to reveal the mechanism of how Vpu removes the antiviral tether from the human cell surface.