Areas of Interest
The rapid evolution of RNA viruses makes them particularly challenging targets for vaccines and antiviral drugs. However, a clearer understanding of their unique evolutionary dynamics may suggest novel approaches for control. Our research objective is to understand mechanisms of viral evolution as they relate to transmission and pathogenesis in infected hosts. We study aspects of evolutionary theory in the context of the host-pathogen interface using molecular virology, small animal models, and sequence data from clinical specimens.
We are particularly interested in aspects of mutation rate and mutational tolerance in poliovirus, influenza, and other RNA viruses. These viruses have extremely high mutation rates, which ensures that the vast majority of newly replicated genomes will be genetically distinct. High mutation rates are clearly a mixed blessing, however, since work in a number of systems indicates that most mutations are either lethal or highly detrimental to viral fitness. Therefore, a virus’ ability to buffer the negative impact of mutation may be an important contributor to its overall fitness. Consistent with this model, we have found that codon usage can influence the mutational robustness of poliovirus, its fitness in vitro, and its ability to spread within an infected host. More recently, we have studied the mutational tolerance of influenza virus and found that transversion mutations are generally more damaging than transitions.
Our findings of mutational hypersensitivity in RNA viruses have led us to re-examine models of mutation rate evolution. Since most mutations are deleterious and mutation rates are tuned by natural selection, why hasn’t the virus evolved to have a lower mutation rate? To answer this question, we have developed a novel assay for viral mutation rates that provides precise measurements for the rates of each mutational class (A to G, U to C etc.). We have used experimental evolution of poliovirus to show that high mutation rates are not in themselves adaptive for the virus. Rather, our data indicate that viral mutation rates are driven higher as a result of selection for viruses with faster replication kinetics. We suggest that viruses have high mutation rates because fidelity imposes a high energetic cost.
Our studies of mutation rates have led us to develop a number of methods for measuring viral diversity within hosts, which we are now using to understand influenza virus dynamics in natural human infections. We have developed and empirically validated a next generation sequencing analysis pipeline to identify intrahost single nucleotide variants at ≥1% frequency in clinical specimens with ≥99.9% specificity. We have used this pipeline to analyze viruses collected as part of a randomized, placebo-controlled trial of vaccine efficacy. This large study of natural infections over 5119 person-years of observation defined the impact of vaccine-induced immunity on intrahost populations. Building on this success, we have an ongoing collaboration with colleagues at the School of Public Health to use deep sequencing of viruses from individuals in a household cohort to infer transmission events and to quantify the transmission bottleneck for respiratory viruses. By defining key population genetic parameters for influenza viruses in natural human infections, we hope to inform models of viral spread in households and communities.
Rohn, JL, Lauring, AS, Linenberger, ML, and Overbaugh, J (1996) Transduction of Notch2 by feline leukemia virus in infected cats with thymic lymphoma. Journal of Virology, 70(11): 8071-8080.
Collins, RN, Brennwald, P, Garrett, M, Lauring, AS, and Novick, P (1997) Interactions of nucleotide release factor Dss4p with Sec4p in the post-Golgi secretory pathway of yeast. Journal of Biological Chemistry, 272(29): 18281-18289.
Anderson, MM, Lauring, AS, Burns, CC, and Overbaugh, J (2000) Identification of a cellular cofactor required for infection by feline leukemia virus. Science, 287(5459): 1828-1830.
Gwynn, SR, Hankenson, FC, Lauring, AS, Rohn, JL, and Overbaugh, J (2000) Feline leukemia virus sequences that affect T-cell tropism and syncytia formation are not part of known receptor binding domains. Journal of Virology, 74 (13): 5754-5761.
Lauring, AS and Overbaugh, J (2000) Evidence that an IRES within the Notch2 coding region can direct expression of a nuclear form of the protein. Molecular Cell, 6(4): 939-945. <p>
Lauring, AS, Anderson, MM, and Overbaugh, J (2001) Specificity in receptor usage by FeLV-T: implications for the in vivo tropism of immunodeficiency-inducing variants. Journal of Virology, 75(19): 8888-8898.
Anderson, MM, Lauring, AS, Robertson, S, Dirks, C, and Overbaugh, J (2001) Feline Pit2 functions as a receptor for subgroup B feline leukemia viruses. Journal of Virology, 75(22):10563-72
Lauring, AS, Cheng, HH, Eiden, MV, and Overbaugh, J (2002) Genetic and biochemical analyses of Pit1 determinants for FeLV-T suggest a novel mechanism for entry. Journal of Virology, 76(16):8069-77.
Graber, C, Lauring, AS, Chin-Hong, PV (2007) Clinical Problem Solving: A Stitch in Time. The New England Journal of Medicine, 357(10):65-70.
Webster, DR*, Hekele, A*, Lauring, AS, Fischer K, Li, H, Andino, R, and DeRisi, J (2009) An enhanced single base extension technique for the analysis of complex viral populations. PLoS One, 4(10):e7453.
Lauring, AS*, Jones, JO*, and Andino, R (2010) Rationalizing the development of live attenuated virus vaccines. Nature Biotechnology, 28(6):573-579.
Lauring, AS and Andino, R (2010) Quasispecies theory and the behavior of RNA viruses, PLoS Pathogens, 6(7):e1001005.
Lauring, AS and Andino, R (2011) Exploring the fitness landscape of an RNA virus by using a universal barcode microarray, Journal of Virology 85(8):3780-3791.
Lauring, AS, Acevedo, A, Bigelow, H, and Andino, R (2012) Codon usage determines the mutational robustness, evolutionary capacity and virulence of an RNA virus, Cell Host Microbe 12(5):623-32.
Lauring, AS, Lee, TH, Martin, JN, Hunt, PW, Deeks, SG, and Busch, M (2012) Lack of evidence for mtDNA as a biomarker of innate immune activation in HIV infection. PLoS One 7(11):e50486.
McCrone JT and Lauring AS* (2016) Measurements of intrahost diversity are extremely sensitive to systematic errors in variant calling, Journal of Virology, 90(15):6884-6695. Selected for Spotlight feature by the editors.
Presloid JB, Mohammad TF, Lauring AS*†, Novella IS*† (2016) Antigenic diversification is correlated with increased thermostability in a mammalian virus, Virology, 496:203-214. Selected for Journal Highlights feature by the editors.
Petrie JG, Ohmit SE, Cheng CK, Martin ET, Malosh RE, Lauring AS, Lamerato L, Reyes KC, Flannery B, Ferdinands JM, Monto AS (2016) Influenza vaccine effectiveness against antigenically drifted influenza higher than expected in hospitalized adults: 2014-2015, Clinical Infectious Diseases, 63(8):1017-1025.
Visher E†, Whitefield SE†, McCrone JT, Fitzsimmons W, Lauring AS* (2016) The mutational robustness of influenza A virus, PLoS Pathogens, 12(8):e1005856.
Debbink K†, McCrone JT†, Petrie JG, Truscon R, Johnson E, Mantlo EK, Monto AS, Lauring AS* (2017) Vaccination has minimal impact on the intrahost diversity of influenza virus, PLoS Pathogens, 13(1):e1006194.
Pauly MD, Procario MC, and Lauring AS* (2017) A novel twelve class fluctuation test reveals higher than expected mutation rates for influenza A viruses, eLife, 6:e26437. See Commentary.
Pauly MD, Lyons DM, Fitzsimmons W, and Lauring AS* (2017) Epistatic interactions within the influenza A virus polymerase complex mediate mutagen resistance and replication fidelity, mSphere 2(4):e00323-17.
Lyons DM and Lauring AS* (2017) Evidence for the selective basis of transition- transversion substitution bias in two RNA viruses, Molecular Biology and Evolution, Sep 25. doi: 10.1093/molbev/msx251.
Malosh RE, Martin ET, Callear AP, Petrie JG, Lauring AS, Lamerato L, Fry AM, Ferdinands J, Flannery B and Monto AS (2017) Respiratory syncytial virus hospitalization in middle-aged and older adults, Journal of Clinical Virology, 96:37-43.
McCrone JT and Lauring AS ( 2018) Genetic bottlenecks in intraspecies virus transmission, Current Opinion in Virology, 28:20-25.
McCrone JT, Woods RJ, Malosh RE, Martin ET, Monto AS, and Lauring AS (2018) Stochastic forces constrain the within and between host evolution of influenza virus. eLife, 7:e35962.
Peck KM and Lauring AS (2018) The complexities of virus mutation rates. Journal of Virology 92(14):e01031-17.
Fitzsimmons W, Woods RJ, McCrone JT, Woodman A, Arnold JJ, Yennawar M, Evans R, Cameron CE, Lauring AS A speed-fidelity trade-off determines the mutation rate and virulence of an RNA virus. PLoS Biology 16(6):e2006459.