Research Theme: Accessory and Regulatory Complexes

Throughout the HIV life cycle, viral-host complexes play an integral role in the biology of the virus. Assemblies range from binary protein-protein and protein-nucleic acid complexes to much larger multicomponent complexes. High-resolution structures of these complexes offer the potential for targeted intervention strategies in the treatment of AIDS.

The HARC Center is structured around five Projects that involve regulatory and accessory proteins that harness host cell machinery to efficiently produce new virions: Integrase, Tat, Rev, Vif and Nef. These proteins mediate key early lifecycle events, and operate by forming complexes with nucleic acids and/or proteins.

In some cases, molecular compositions of complexes between HIV proteins and host partners are known. In other cases, details of the complexes remain to be identified. Many of the HIV proteins form interactions with more than one protein and some complexes may exist only transiently. Thus, an important element of our research program is the Mass Spectroscopy and Protein Expression Core, which will use a powerful technique derived from proteomics in yeast--tandem affinity purification and mass spectroscopy--to validate known complexes and identify novel interactions.

Once target complexes are validated or new complexes are identified, the Center is well-positioned to apply high-throughput protein expression and purification techniques, along with a full range of functional and biophysical characterization, and structural analysis using NMR, crystallography, cryo-EM and computational techniques.

Each of the HARC Center projects will answer important structural questions about changes in conformation and dynamics upon binding macromolecular partners. Each also presents potential novel drug targets that would expand the repertoire of effective HIV treatments.