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Research Interests: Molecular mechanisms of viral replication, host interactions and oncogenesis.

Research Description: We are studying the novel, RNA-based pathways and virus-host interactions underlying replication, gene expression and evolution by positive-strand RNA viruses, the largest class of viruses. Positive strand RNA viruses include many important human pathogens such as hepatitis C virus, which chronically infects nearly 3% of the world population, causing progressive liver damage and liver cancer, and the new SARS coronavirus. We are also studying selected replication processes of a reverse-transcribing virus, hepatitis B virus, which is also a major human tumor virus. Our studies integrate molecular genetics, genomics, biochemistry and cell biology to address fundamental questions in virus replication and virus-cell interactions.

Viruses are divided into six distinct classes differing in the type of nucleic acid in the virus particle and its replication pathways. Recently, we discovered multiple, detailed structural and functional parallels among the replication complexes of three of these six virus classes: positive-strand RNA viruses, retroviruses and dsRNA viruses. These results imply a significant functional and evolutionary unification within virology, and have opened the door to many exciting new experimental questions and approaches that we are now pursuing.

We also have identified the first higher eukaryotic viruses that can direct genome replication, gene expression and virion assembly in the genetically tractable yeast Saccharomyces cerevisiae. Using yeast genetics and genomics, we are identifying a growing number of host genes required for viral RNA replication and are studying how these function with virus-encoded helicase- and polymerase-like replication factors and diverse cis-acting viral RNA signals to direct assembly and function of the membrane-bound viral genome replication complexes and other processes.

Selected recent publications

Hao, L., Sakurai, A., Watanabe, T., Sorensen, E., Nidom, C. A., Newton, M. A., Ahlquist, P., and Kawaoka, Y.  Drosophila RNAi Screen Identifies Host Genes Important for Influenza Virus Replication.  Nature, 454:  890-893, 2008.

Sengupta, S., den Boon, J. A., Chen, I.-H., Newton, M. A., Stanhope, S. A., Cheng, Y.-J., Chen, C.-J., Hildesheim, A., Sugden, B., and Ahlquist, P.  MicroRNA 29c Is Down-regulated in Nasopharyngeal Carcinomas, Up-regulating mRNAs Encoding Extracellular Matrix Proteins.  Proc. Natl. Acad. Sci. USA, 105:  5874-5878, 2008.

Wang, X., and Ahlquist, P.  Filling a GAP(DH) in Asymmetric Viral RNA Synthesis.  Cell Host & Microbe, 3:  124-125, 2008.

Beckham, C. J., Light, H. R., Nissan, T. A., Ahlquist, P., Parker, R., and Noueiry, A.  Interactions between Brome Mosaic Virus RNAs and Cytoplasmic Processing Bodies.  J. Virol., 81:  9759-9768, 2007.

Kopek, B. G., Perkins, G., Miller, D. J., Ellisman, M. H., and Ahlquist, P.  Three-Dimensional Analysis of a Viral RNA Replication Complex Reveals a Virus-Induced Mini-Organelle.  PLoS Biol., 5:e220, 2007.

Newton, M. A., Quintana, F. A., den Boon, J. A., Sengupta, S., and Ahlquist, P.  Random-Set Methods Identify Distinct Aspects of the Enrichment Signal in Gene-Set Analysis.  Ann. Appl. Stat., 1:  85-106, 2007.

Pyeon, D., Newton, M. A., Lambert, P. F., den Boon, J. A., Sengupta, S., Marsit, C. J., Woodworth, C. D., Connor, J. P., Haugen, T. H., Smith, E. M., Kelsey, K. T., Turek, L. P., and Ahlquist, P.  Fundamental Differences in Cell Cycle Deregulation in Human Papillomavirus-Positive and Human Papillomavirus-Negative Head/Neck and Cervical Cancers.  Cancer Res., 67:  4605-4619, 2007.

Van Wynsberghe, P. M., Chen, H.-R., and Ahlquist, P.  Nodavirus RNA Replication Protein A Induces Membrane Association of Genomic RNA.  J. Virol., 81:  4633-4644, 2007.

Watanabe, T., Sorensen, E. M., Naito, A., Schott, M., Kim, S., and Ahlquist, P.  Involvement of Host Cellular Multivesicular Body Functions in Hepatitis B Virus Budding.  Proc. Natl. Acad. Sci. USA, 104:  10205-10210, 2007.

Ahlquist, P. Parallels Among Positive-strand RNA Viruses, Reverse-transcribing Viruses and Double-stranded RNA Viruses. Nat. Rev. Microbiol., 4: 371-382, 2006.

Dodd, L. E., Sengupta, S., Chen, I.-H., den Boon, J. A., Cheng, Y.-J., Westra, W., Newton, M. A., Mittl, B. F., McShane, L., Chen, C.-J., Ahlquist, P., and Hildesheim, A.  Genes Involved in DNA Repair and Nitrosamine Metabolism and Those Located on Chromosome 14q32 Are Dysregulated in Nasopharyngeal Carcinoma.  Cancer Epidemiol. Biomarkers Prev., 15:  2216-2225, 2006.

Garcia-Ruiz, H., and Ahlquist P.  Inducible Yeast System for Viral RNA Recombination Reveals Requirement for an RNA Replication Signal on Both Parental RNAs.  J. Virol., 80:  8316-8328, 2006.

Mas, A., Alves-Rodrigues, I. , Noueiry, A., Ahlquist, P., and Díez, J. Host Deadenylation-Dependent mRNA Decapping Factors Are Required for a Key Step in Brome Mosaic Virus RNA Replication. J. Virol., 80: 246-251, 2006.

Sengupta, S., den Boon, J. A., Chen, I.-H., Newton, M. A., Dahl, D. B., Chen, M., Cheng, Y.-J., Westra, W. H., Chen, C.-J., Hildesheim, A., Sugden, B., and Ahlquist, P.  Genome-Wide Expression Profiling Reveals EBV-Associated Inhibition of MHC Class I Expression in Nasopharyngeal Carcinoma.  Cancer Res., 66:  7999-8006, 2006.

Ahlquist, P. Virus Evolution: Fitting Lifestyles to a T. Curr. Biol., 15: R465-R467, 2005.

Ahlquist, P., Schwartz, M., Chen, J., Kushner, D., Hao, L., and Dye, B. T. Viral and Host Determinants of RNA Virus Vector Replication and Expression. Vaccine, 23: 1784-1787, 2005.

Bruce, J. W., Bradley, K. A., Ahlquist, P., and Young, J. A. T. Isolation of Cell Lines That Show Novel, Murine Leukemia Virus-Specific Blocks to Early Steps of Retroviral Replication. J. Virol., 79: 12969-12978, 2005.

Dye, B. T., Hao, L., and Ahlquist, P. High-throughput Isolation of Saccharomyces cerevisiae RNA. BioTechniques, 38: 868-870, 2005.

Dye, B. T., Miller, D. J., and Ahlquist, P. In Vivo Self-Interaction of Nodavirus RNA Replicase Protein A Revealed by Fluorescence Resonance Energy Transfer. J. Virol., 79: 8909-8919, 2005.

Dye, B. T., Schell, K., Miller, D. J., and Ahlquist, P. Detecting Protein-Protein Interaction in Live Yeast by Flow Cytometry. Cytometry Part A, 63A: 77-86, 2005.

Grdzelishvili, V. Z., Garcia-Ruiz, H., Watanabe, T., and Ahlquist, P. Mutual Interference between Genomic RNA Replication and Subgenomic mRNA Transcription in Brome Mosaic Virus. J. Virol., 79: 1438-1451, 2005.

Perrigoue, J. G., den Boon, J. A., Friedl, A., Newton , M. A., Ahlquist, P., and Sugden, B. Lack of Association between EBV and Breast Carcinoma. Cancer Epidemiol. Biomarkers Prev., 14: 809-814, 2005.

Pyeon, D., Lambert, P. F., and Ahlquist, P. Production of Infectious Human Papillomavirus Independently of Viral Replication and Epithelial Cell Differentiation. Proc. Natl. Acad. Sci. USA, 102: 9311-9316, 2005.

Wang, X., Lee, W.-M., Watanabe, T., Schwartz, M., Janda, M., and Ahlquist, P. Brome Mosaic Virus 1a Nucleoside Triphosphatase/Helicase Domain Plays Crucial Roles in Recruiting RNA Replication Templates. J. Virol., 79: 13747-13758, 2005.

Newton, M. A., Noueiry, A., Sarkar, D., and Ahlquist, P. Detecting Differential Gene Expression with a Semiparametric Hierarchical Mixture Method. Biostatistics, 5: 155-176, 2004.

Schwartz, M., Chen, J., Lee, W.-M., Janda, M., and Ahlquist, P. Alternate, Virus-induced Membrane Rearrangements Support Positive-strand RNA Virus Genome Replication. Proc. Natl. Acad. Sci. USA, 101: 11263-11268, 2004.

Ahlquist, P., Noueiry, A. O., Lee, W.-M., Kushner, D. B., and Dye, B. T. Host Factors in Positive-Strand RNA Virus Genome Replication. J. Virol., 77: 8181-8186, 2003.

Chen, J., Noueiry, A., and Ahlquist, P. An Alternate Pathway for Recruiting Template RNA to the Brome Mosaic Virus RNA Replication Complex. J. Virol., 77: 2568-2577, 2003.

Kushner, D. B., Lindenbach, B. D., Grdzelishvili, V. Z., Noueiry, A. O., Paul, S. M., and Ahlquist, P. Systematic, Genome-Wide Identification of Host Genes Affecting Replication of a Positive-Strand RNA Virus. Proc. Natl. Acad. Sci. USA, 100: 15764-15769, 2003.

Lee, W.-M., and Ahlquist, P. Membrane Synthesis, Specific Lipid Requirements, and Localized Lipid Composition Changes Associated with a Positive-Strand RNA Virus RNA Replication Protein. J. Virol., 77: 12819-12828, 2003.

Miller, D. J., Schwartz, M. D., Dye, B. T., and Ahlquist, P. Engineered Retargeting of Viral RNA Replication Complexes to an Alternative Intracellular Membrane. J. Virol., 77: 12193-12202, 2003.

Noueiry, A. O., and Ahlquist, P. Brome Mosaic Virus RNA Replication: Revealing the Role of the Host in RNA Virus Replication. Annu. Rev. Phytopathol., 41: 77-98, 2003.

Noueiry, A. O., Diez, J., Falk, S. P., Chen, J., and Ahlquist, P. Yeast Lsm1p-7p/Pat1p Deadenylation-Dependent mRNA-Decapping Factors Are Required for Brome Mosaic Virus Genomic RNA Translation. Mol. Cell Biol., 23: 4094-4106, 2003.

Tomita, Y., Mizuno, T., Díez, J., Naito, S., Ahlquist, P., and Ishikawa, M. Mutation of Host dnaJ Homolog Inhibits Brome Mosaic Virus Negative-Strand RNA Synthesis. J. Virol., 77: 2990-2997, 2003.

Ahlquist, P. RNA-Dependent RNA Polymerases, Viruses, and RNA Silencing. Science, 296:1270-1273, 2002.

Lindenbach, B. D., Sgro, J.-Y., and Ahlquist, P. Long-Distance Base Pairing in Flock House Virus RNA1 Regulates Subgenomic RNA3 Synthesis and RNA2 Replication. J. Virol., 76: 3905-3919, 2002.

Miller, D. J., and Ahlquist, P. Flock House Virus RNA Polymerase Is a Transmembrane Protein with Amino-Terminal Sequences Sufficient for Mitochondrial Localization and Membrane Insertion. J. Virol., 76: 9856-9867, 2002.

Price, B. D., Ahlquist, P., and Ball, L. A. DNA-Directed Expression of an Animal Virus RNA for Replication-Dependent Colony Formation in Saccharomyces cerevisiae. J. Virol., 76: 1610-1616, 2002.

Schwartz, M., Chen, J., Janda, M., Sullivan, M., den Boon, J., and Ahlquist, P. A Positive-Strand RNA Virus Replication Complex Parallels Form and Function of Retrovirus Capsids. Mol. Cell, 9: 505-514, 2002.

Baumstark, T., and Ahlquist, P. The Brome Mosaic Virus RNA3 Intergenic Replication Enhancer Folds to Mimic a tRNA TYC-Stem Loop and Is Modified in Vivo. RNA, 7: 1652-1670, 2001.

Chen J., Noueiry, A., and Ahlquist, P. Brome Mosaic Virus Protein 1a Recruits Viral RNA2 to RNA Replication through a 5´ Proximal RNA2 Signal. J. Virol., 75: 3207-3219, 2001.

den Boon, J. A., Chen, J., and Ahlquist, P. Identification of Sequences in Brome Mosaic Virus Replicase Protein 1a That Mediate Association with Endoplasmic Reticulum Membranes. J. Virol., 75: 12370-12381, 2001.

Lee, W.-M., Ishikawa, M., and Ahlquist, P. Mutation of Host D9 Fatty Acid Desaturase Inhibits Brome Mosaic Virus RNA Replication between Template Recognition and RNA Synthesis. J. Virol., 75: 2097-2106, 2001.

Miller, D. J., Schwartz, M. D., and Ahlquist, P. Flock House Virus RNA Replicates on Outer Mitochondrial Membranes in Drosophila Cells. J. Virol., 75: 11664-11676, 2001.

Ahola, T., den Boon, J., and Ahlquist, P. Helicase and Capping Enzyme Active Site Mutations in Brome Mosaic Virus Protein 1a Cause Defects in Template Recruitment, Negative-Strand RNA Synthesis and Viral RNA Capping. J. Virol., 74: 8803-8811, 2000.

Chen, J., and Ahlquist, P. Brome Mosaic Virus Polymerase-like Protein 2a is Directed to the Endoplasmic Reticulum by Helicase-like Viral Protein 1a. J. Virol., 74: 4310-4318, 2000.

Diez, J., Ishikawa, M., Kaido, M., and Ahlquist, P. Identification and Characterization of a Host Protein Required for Efficient Template Selection in Viral RNA Replication. Proc. Natl. Acad. Sci. USA, 97: 3913-3918, 2000.

Ishikawa, M., Janda, M., and Ahlquist, P. 3a Cell-to-Cell Movement Gene Is Dispensable for Cell-Cell Transmission of Brome Mosaic Virus RNA Replicons in Yeast but Retained over 10⁴⁵-fold Amplification. J. Gen. Virol. 81: 2307-2311, 2000.

Noueiry, A., Chen, J., and Ahlquist, P. A Mutant Allele of Essential, General Translation Initiation Factor DED1 Selectively Inhibits Translation of a Viral mRNA. Proc. Natl. Acad. Sci. USA, 97: 12985-12990, 2000.

Price, B. D., Roeder, M., and Ahlquist, P. DNA-directed Expression of Functional Flock House Virus RNA1 Derivatives in Saccharomyces cerevisiae, Heterologous Gene Expression, and Selective Effects on Subgenomic mRNA Synthesis. J. Virol., 74: 11724-11733, 2000.

Ahola, T., and Ahlquist, P. Putative RNA Capping Activities Encoded by Brome Mosaic Virus: Methylation and Covalent Binding of Guanylate by Replicase Protein 1a. J. Virol., 73: 10061-10069, 1999.

Krol, M., Olson, N., Tate, J., Johnson, J., Baker, T., and Ahlquist, P. RNA-Controlled Polymorphism in the in Vivo Assembly of 180-Subunit and 120-Subunit Virions from a Single Capsid Protein. Proc. Natl. Acad. Sci. USA, 96: 13650-13655, 1999.

Restrepo-Hartwig, M., and Ahlquist, P. Brome Mosaic Virus RNA Replication Proteins 1a and 2a Colocalize and 1a Independently Localizes on the Yeast Endoplasmic Reticulum. J. Virol., 73: 10303-10309, 1999.

Sullivan, M., and Ahlquist, P. A Brome Mosaic Virus Intergenic RNA3 Replication Signal Functions with Viral Replication Protein 1a to Dramatically Stabilize RNA in Vivo. J. Virol., 73: 2622-2632, 1999.

Janda, M., and Ahlquist, P. Brome Mosaic Virus RNA Replication Protein 1a Dramatically Increases in Vivo Stability but not Translation of Viral Genomic RNA3. Proc. Natl. Acad. Sci. USA, 95: 2227-2232, 1998.

Ishikawa, M., Diez, J., Restrepo-Hartwig, M., and Ahlquist, P. Yeast Mutations in Multiple Complementation Groups Inhibit Brome Mosaic Virus RNA Replication and Transcription and Perturb Regulated Expression of the Viral Polymerase-like Gene. Proc. Natl. Acad. Sci. USA, 94: 13810-13815, 1997.

Ishikawa, M., Janda, M., Krol, M., and Ahlquist, P. In Vivo DNA Expression of Functional Brome Mosaic Virus RNA Replicons in Saccharomyces cerevisiae. J. Virol., 71: 7781-7790, 1997.

Price, B. D., Rueckert, R., and Ahlquist, P. Complete Replication of an Animal Virus and Maintenance of Expression Vectors derived from it in Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA, 93: 9465-9470, 1996.

Restrepo-Hartwig, M., and Ahlquist, P. Brome Mosaic Virus Helicase- and Polymerase-like Proteins Colocalize on the Endoplasmic Reticulum at Sites of Viral RNA Synthesis. J. Virol., 70: 8908-8916, 1996.

Smirnyagina, E., Lin, N. S., and Ahlquist, P. The Polymerase-like Core of Brome Mosaic Virus 2a Protein, Lacking a Region Interacting with Viral 1a Protein in Vitro, Maintains Activity and 1a Selectivity in RNA Replication. J. Virol., 70: 4729-4736, 1996.