Understanding the structural interactions of HIV assembly, maturation and replication is critical to linking the current structural knowledge of two of the major enzymatic targets, HIV protease and reverse transcriptase, with their polyprotein precursors, substrates and effectors. Expanding the evolving structural knowledge of the HIV integrase and its interactions with host proteins will provide a more complete picture of the mechanisms of the third major drug target. We have formed the HIV Interaction and Viral Evolution (HIVE) Center to characterize at the atomic level the structural and dynamic relationships between interacting macromolecules in the HIV life cycle. We will focus on interactions of the major HIV enzymes with their partners and effectors since they encompass key processes in the viral life cycle and as existing drug targets provide a rich base of structural, biological and evolutionary data that will serve to inform our goals. We will explore resistance evolution in HIV as an opportune platform upon which to characterize the dynamic relationships between interacting macromolecular structures at the atomic level. Our approach is significant due to the promise of new structural insights into the interdependence of viral mechanisms and the direct potential for new drug design methodologies and therapeutic strategies.
The HIVE Center comprises a group of investigators with expertise in HIV crystallography, virology, molecular biology, biochemistry, synthetic chemistry and computational biology. We will study the mechanistic implications of viral macromolecular interactions and dynamics and its broader impacts of the evolution of drug resistance to address several biological questions:
- How do structures of the HIV polyprotein precursors direct assembly, maturation, and replication?
- What novel HIV–Host interactions drive DNA replication and integration?
- How does dynamics impact viral function and fitness and how can it be exploited for therapeutic targeting?
- What are the structural and dynamic consequences of resistance mutations in the HIV life cycle?
Arthur OlsonDirector Arthur J. Olson brings to the Center two decades of research and development in computational docking and virtual screening, and the largest distributed-computing resource currently addressing HIV biology: FightAIDS@Home.
The HIVE Center characterizes assemblies of HIV and host molecules in multiple states and their transitions, by combining structural studies of HIV protein interactions with chemical and evolutionary probes and computational modeling to elucidate macromolecular interactions and mechanisms critical for the viral life cycle. Previous work by Center structural biologists have characterized all of the HIV enzymes, with over 300 unique structure depositions in the PDB, and the work within HIVE will reveal their interaction and maturation from viral polyproteins, and their interactions within the viral lifecycle. HIVE laboratories are approaching this challenge with a variety of experimental methods. The evolution of HIV under the selection pressure of small molecule effectors provides a functional window on the underlying macromolecular interactions. Chemistry gives us the capability to design and refine new atomic level probes to explore mechanism. Computational modeling guides the establishment of structural hypotheses and enables the integration of multi-scale dynamic data into a coherent physical picture.