HIV Macromolecular Interactions and Impact on Viral Evolution of Drug Resistance

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DESCRIPTION (provided by applicant): We have formed the 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 infom 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. The HIVE Center comprises a group of investigators with considerable expertise in HIV crystallography, virology, molecular biology, 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. The goals of this center are to answer the following fundamental questions with our studies: 1. How do structures of the HIV polyprotein precursors direct assembly, maturation, and replication? 2. What novel HIV-Host interactions drive DNA replication and integration? 3. How does dynamics impact viral fitness and how can it be exploited for therapeutic targeting? 4. What are the structural and dynamic consequences of resistance mutations in the HIV life cycle, and how? In order to carry out these studies we will develop, improve and apply the following Technical Methods for: 1. Efficient expression, crystallization, and atomic level structure determination of HIV polyprotein and nucleic acid complexes. 2. Determination and characterization of novel binding sites and their impact on the dynamic and evolutionary properties of HIV protein complexes. 3. Computational methods to characterize the interactions, dynamics and evolution of HIV protein complexes at multiple spatial and temporal scales. Our approach is significant both for the promise of new structural insights into the interdependence of viral mechanisms, but also for the direct potential for new drug design methodologies and therapeutic strategies.