Background

The HIV Interaction and Viral Evolution (HIVE) Center is a multi-institute research consortium led by Arthur Olson at The Scripps Research Institute La Jolla, CA. The HIVE Center integrates the efforts of 15 research groups representing leaders in the field of HIV structural biology. Our goal is high-resolution characterization of the structural and dynamic relationships among interacting macromolecules in the HIV life cycle.

The HIVE Center’s core goal is a comprehensive structural depiction of the major HIV enzyme’s (protease, reverse transcriptase, integrase) interactions with their viral and host partners during viral assembly, maturation, replication, and integration. As existing drug targets, they provide arich base of structural, biological, and evolutionary data that will serve to inform our far-reaching goals. We also propose to explore resistance and evolution in HIV as a platform upon which to characterize the dynamic relationships among interacting macromolecular structures.

Our approach encompasses diverse disciplines and methodologies including computation, crystallography, hydrogen-deuterium exchange, eukaryotic cell-based protein expression, synthetic chemistry, and virology. It is geared toward gaining new structural insights into the interdependence of viral-host mechanisms and the potential for using this information for new drug design methods and therapeutic strategies.

Some of the specific features of the HIV life cycle that remain incompletely characterized from a structural vantage point that we wish to address are: 1) structures of the HIV Gag, Gag-Pol, and Pol polyprotein precursors; 2) molecular structures of the HIV transcription initiation complex with HIV RT, host tRNA, and viral RNA; 3) structure and interactions of the HIV intasome with protein and nucleic acid host factors; and 4) conformational dynamics of HIV proteins and their complexes probed by small-molecule allosteric effectors and inhibitors.

Application

The HIVE center is currently seeking collaborators to join us in working to characterize and understand the structural and dynamic viral-host interactions of HIV polyprotein precursors and their mature enzyme counterparts during key stages of the HIV life cycle.

Interested applicants are required to contact a HIVE Center member to sponsor their application.

A brief summary of the proposed work and how it will contribute to the HIVE Center’s research objectives must be included in the HIVE Center face page submitted with their application (see application details below). Investigators at an early stage in their career and/or new to HIV research are strongly encouraged to apply. We will accept proposals for review from eligible applicants that contribute complementary or overlapping methods. Some examples include but are not limited to:

• Imaging of Gag/Gag-Pol polyprotein precursors and of HIV-host complexes by cryoelectron microscopy/tomography, SAXS/SANS, NMR, or other techniques
• Single molecule and ensemble FRET-based assays for exploring structural dynamics of viral and viral-host protein-protein and protein-nucleic acid complexes
• Stopped-flow and rapid-quench measurements of kinetic parameters of viral-catalyzed processes and viral-host component interactions
• Ex vivo and mathematical modeling approaches to explore HIV drug resistance and evolution

Funding: Grants of approximately $50,000 (direct costs) will be awarded to 2 or 3 investigators each funding cycle for up to two years. Funding for the second year will depend upon progress in the first year.

The deadline for proposals is midnight (EST) May 1, 2014. Notifications will be sent out by July 1, 2014 with funding to start on September 1, 2014.
Proposals should be submitted electronically as PDF files to Dr. Steve Tuske (tuske@cabm.rutgers.edu) and include a plan of collaboration as discussed with a sponsoring HIVE Center investigator.

Eligibility: Faculty at the level of Assistant Professor or higher who are eligible for NIH funding.
Women, minorities, veterans, and disabled persons are encouraged to apply.

Format: Single-spaced, ½-inch margins, Arial typeface, font size 12
Required Components (in indicated order):
HIVE Center face page that includes a statement of collaboration and sponsoring HIVE Center member.
Detailed Budget and Budget Justification
NIH Biosketch (4 page maximum)
Proposal Text (sections A – D, 4 pages total)
A. Specific Aim(s)
B. Background
C. Preliminary Data
D. Research Design and Methods
E. Timeline and Specific Milestone(s) (Not to exceed 1 page)
F. References Cited

Questions: Questions about the application and review processes should be directed to Dr. Steve Tuske: tuske@cabm.rutgers.edu or (732) 235-4064.

Funded Individuals:
Funded investigators will be required to follow all NIH regulations/requirements, including those related to animal use, human subjects, recombinant DNA, biohazards, select agents, and reporting. In addition, participation in HIVE Center activities, including monthly teleconferences, meetings and annual symposia is required.

HIVE Collaborators (2012-2014):
John Tainer and Jefferson Perry, The Scripps Research Institute La Jolla, Advanced SAXS technologies for HIVE center studies
Stefanos Sarafianos and Kamlendra Singh, University of Missouri, Rilpivirine Inhibition of Initiation of HIV Reverse Transcription: A pre-steady state kinetics approach
James Fuchs, Ohio State University, Optimization of FBDD derived leads as allosteric HIV integrase inhibitors