Essentially every step in the HIV life cycle interfaces intimately with the host cell machinery. The Pittsburgh Center of HIV Protein Interactions will focus on the steps and interactions that occur with the host after engagement of cell surface receptors and membrane fusion and before integration of the viral genome into that of the host, the so called """"""""early events"""""""". Several essential molecular interactions and enzymatic activities occur within this time window, necessary for productive progression of the viral life cycle. Thus, it represents a pivotal period in the infection process, during which the susceptibility of the virs to disruptive interventions is likely to be high and little explored. Broadly speaking, the processes that we will focus on include capsid disassembly (uncoating), reverse transcription, evasion of innate immune factors, and nuclear entry. Given the importance of the capsid structure and its interactions for many of these processes, we have expanded capsid studies to include an analysis of CA protein maturation and capsid formation. We plan to build on our successes and apply the extensive and complementary experimental expertise of our team to carry out 1) biochemical and high-resolution structure studies of individual proteins and complexes, 2) proteomics analyses to identify novel interactions and complexes, 3) virology and imaging studies to understand protein function in the context of the cell and virus infection, 4) sequence analyses of evolutionary correlations in protein interactions and dynamics, and 5) computational analyses to generate an all-atom model of the HIV-1 capsid and to elucidate the physical basis of uncoating (the process by which the capsid disassembles). Further, we plan to extend our Correlative Imaging Technology Development Program to develop specific probes and tools for exploring the dynamics of HIV-1 and associated proteins during cellular infection

Public Health Relevance

Results provided by the proposed research are expected to have major implications in the global fight against AIDS, still considered an incurable disease with a pressing need for new therapeutic strategies and novel drug targets. Identifying and characterizing atomic structures of key HIV-1 host protein interactions in the immediate post-entry stage of the virus lifecycle will open new avenues in this endeavor.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-AARR-K (50))
Program Officer
Sakalian, Michael
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Quinn, Caitlin M; Wang, Mingzhang; Fritz, Matthew P et al. (2018) Dynamic regulation of HIV-1 capsid interaction with the restriction factor TRIM5? identified by magic-angle spinning NMR and molecular dynamics simulations. Proc Natl Acad Sci U S A 115:11519-11524
Varlakhanova, Natalia V; Alvarez, Frances J D; Brady, Tyler M et al. (2018) Structures of the fungal dynamin-related protein Vps1 reveal a unique, open helical architecture. J Cell Biol 217:3608-3624
Ning, Jiying; Zhong, Zhou; Fischer, Douglas K et al. (2018) Truncated CPSF6 Forms Higher-Order Complexes That Bind and Disrupt HIV-1 Capsid. J Virol 92:
Himes, Benjamin A; Zhang, Peijun (2018) emClarity: software for high-resolution cryo-electron tomography and subtomogram averaging. Nat Methods 15:955-961
Balasubramaniam, Muthukumar; Zhou, Jing; Addai, Amma et al. (2018) PF74 Inhibits HIV-1 Integration by Altering The Composition of the Preintegration Complex. J Virol :
Lu, Manman; Sarkar, Sucharita; Wang, Mingzhang et al. (2018) 19F Magic Angle Spinning NMR Spectroscopy and Density Functional Theory Calculations of Fluorosubstituted Tryptophans: Integrating Experiment and Theory for Accurate Determination of Chemical Shift Tensors. J Phys Chem B 122:6148-6155
Kraus, Jodi; Gupta, Rupal; Yehl, Jenna et al. (2018) Chemical Shifts of the Carbohydrate Binding Domain of Galectin-3 from Magic Angle Spinning NMR and Hybrid Quantum Mechanics/Molecular Mechanics Calculations. J Phys Chem B 122:2931-2939
Quinn, Caitlin M; Wang, Mingzhang; Polenova, Tatyana (2018) NMR of Macromolecular Assemblies and Machines at 1 GHz and Beyond: New Transformative Opportunities for Molecular Structural Biology. Methods Mol Biol 1688:1-35
Hadden, Jodi A; Perilla, Juan R (2018) All-atom virus simulations. Curr Opin Virol 31:82-91
Yan, Junpeng; Shun, Ming-Chieh; Hao, Caili et al. (2018) HIV-1 Vpr Reprograms CLR4DCAF1 E3 Ubiquitin Ligase to Antagonize Exonuclease 1-Mediated Restriction of HIV-1 Infection. MBio 9:

Showing the most recent 10 out of 144 publications