CAREER: Structural Interplay Between Chromatin Remodeling and Lentiviral Integration

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This research will uncover how some viruses like HIV hijack host protein machinery and permanently alter the host genome to sustain infection. The work will produce atomic structures that reveal the interactions between viral and host proteins that mediate the integration of viral genetic information into the host genome. The resulting structures and biochemical data will provide a mechanistic framework for understanding how these interactions lead to productive infection and will reveal insights into how this process may be blocked, and lead to novel anti-virals, or can be exploited for gene therapy. These research themes will be taught to audiences at different stages of their scientific development. The integrated research and education plan includes the advanced scientific training of both undergraduate and graduate students, the exposure of students to complex scientific programs within a world-renowned academic research institution, and the introduction of both structural biology and virology to under-privileged high-school students to inspire their scientific development. All lentiviruses, including HIV, are characterized by an important hallmark that distinguishes them from other viruses — their ability to integrate a complementary DNA copy of their RNA genome into target host chromatin through a catalytic process called integration. Integration establishes a permanent and irreversible infection in the target cell and contributes to viral pathogenicity. Although we understand the basic mechanisms underlying lentiviral integration, we know comparatively little about the role that host factors play in this process. Specifically, there is the prominent but wholly underappreciated phenomenon of chromatin remodeling that accompanies successful integration. Disruption of host chromatin remodelers leads to distinct phenotypes affecting lentiviral infection, but how the remodelers are assembled, engage chromatin, and ultimately interplay with lentiviral components to affect integration remain unclear. Using cryogenic electron microscopy and biochemical methods, this research will investigate: (1) how ATP-independent chromatin remodelers reorganize chromatin and exploit this reorganized state to engage viral machinery prior to catalytic integration; and (2) how ATP-dependent chromatin remodelers engage and reorganize integrated viral DNA after catalytic integration to establish a transcriptionally competent provirus. This work will provide a mechanistic molecular framework that elucidates how host chromatin remodelers interact with viral machinery to facilitate integration and establish a foundation for future work that broadly examines the structure, function, and cross-talk between the molecular machines responsible for chromatin remodeling and lentiviral integration.This work was jointly funded by the Molecular Biophysics and Genetic Mechanisms clusters.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.