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J Virol. Jun 1991; 65(6): 2960–2967.
PMCID: PMC240937

Quantitation of relative fitness and great adaptability of clonal populations of RNA viruses.


We describe a sensitive, internally controlled method for comparing the genetic adaptability and relative fitness of virus populations in constant or changing host environments. Certain monoclonal antibody-resistant mutants of vesicular stomatitis virus can compete equally during serial passages in mixtures with the parental wild-type clone from which they were derived. These genetically marked "surrogate wild-type" neutral mutants, when mixed with wild-type virus, allow reliable measurement of changes in virus fitness and of virus adaptation to different host environments. Quantitative fitness vector plots demonstrate graphically that even clones of an RNA virus are composed of complex variant populations (quasispecies). Variants of greater fitness (competitive replication ability) were selected within very few passages of virus clones in new host cells or animals. Even clones which were well adapted to BHK21 cells gained further fitness during repeated passages in BHK21 cells.

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  • Air GM, Gibbs AJ, Laver WG, Webster RG. Evolutionary changes in influenza B are not primarily governed by antibody selection. Proc Natl Acad Sci U S A. 1990 May;87(10):3884–3888. [PMC free article] [PubMed]
  • Batschelet E, Domingo E, Weissmann C. The proportion of revertant and mutant phage in a growing population, as a function of mutation and growth rate. Gene. 1976;1(1):27–32. [PubMed]
  • Bilsel PA, Nichol ST. Polymerase errors accumulating during natural evolution of the glycoprotein gene of vesicular stomatitis virus Indiana serotype isolates. J Virol. 1990 Oct;64(10):4873–4883. [PMC free article] [PubMed]
  • Cattaneo R, Schmid A, Eschle D, Baczko K, ter Meulen V, Billeter MA. Biased hypermutation and other genetic changes in defective measles viruses in human brain infections. Cell. 1988 Oct 21;55(2):255–265. [PubMed]
  • Cohen JI, Rosenblum B, Ticehurst JR, Daemer RJ, Feinstone SM, Purcell RH. Complete nucleotide sequence of an attenuated hepatitis A virus: comparison with wild-type virus. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2497–2501. [PMC free article] [PubMed]
  • de la Torre JC, Wimmer E, Holland JJ. Very high frequency of reversion to guanidine resistance in clonal pools of guanidine-dependent type 1 poliovirus. J Virol. 1990 Feb;64(2):664–671. [PMC free article] [PubMed]
  • DePolo NJ, Giachetti C, Holland JJ. Continuing coevolution of virus and defective interfering particles and of viral genome sequences during undiluted passages: virus mutants exhibiting nearly complete resistance to formerly dominant defective interfering particles. J Virol. 1987 Feb;61(2):454–464. [PMC free article] [PubMed]
  • Domingo E, Dávila M, Ortín J. Nucleotide sequence heterogeneity of the RNA from a natural population of foot-and-mouth-disease virus. Gene. 1980 Nov;11(3-4):333–346. [PubMed]
  • Domingo E, Flavell RA, Weissmann C. In vitro site-directed mutagenesis: generation and properties of an infectious extracistronic mutant of bacteriophage Qbeta. Gene. 1976;1(1):3–25. [PubMed]
  • Domingo E, Martínez-Salas E, Sobrino F, de la Torre JC, Portela A, Ortín J, López-Galindez C, Pérez-Breña P, Villanueva N, Nájera R, et al. The quasispecies (extremely heterogeneous) nature of viral RNA genome populations: biological relevance--a review. Gene. 1985;40(1):1–8. [PubMed]
  • Domingo E, Sabo D, Taniguchi T, Weissmann C. Nucleotide sequence heterogeneity of an RNA phage population. Cell. 1978 Apr;13(4):735–744. [PubMed]
  • Durbin RK, Stollar V. Sequence analysis of the E2 gene of a hyperglycosylated, host restricted mutant of Sindbis virus and estimation of mutation rate from frequency of revertants. Virology. 1986 Oct 15;154(1):135–143. [PubMed]
  • ENDERS JF, KATZ SL, MILOVANOVIC MV, HOLLOWAY A. Studies on an attenuated measles-virus vaccine. I. Development and preparations of the vaccine: technics for assay of effects of vaccination. N Engl J Med. 1960 Jul 28;263:153–159. [PubMed]
  • Fields BN, Joklik WK. Isolation and preliminary genetic and biochemical characterization of temperature-sensitive mutants of reovirus. Virology. 1969 Mar;37(3):335–342. [PubMed]
  • Fisher AG, Ensoli B, Looney D, Rose A, Gallo RC, Saag MS, Shaw GM, Hahn BH, Wong-Staal F. Biologically diverse molecular variants within a single HIV-1 isolate. Nature. 1988 Aug 4;334(6181):444–447. [PubMed]
  • Gebauer F, de la Torre JC, Gomes I, Mateu MG, Barahona H, Tiraboschi B, Bergmann I, de Mello PA, Domingo E. Rapid selection of genetic and antigenic variants of foot-and-mouth disease virus during persistence in cattle. J Virol. 1988 Jun;62(6):2041–2049. [PMC free article] [PubMed]
  • Gojobori T, Yokoyama S. Rates of evolution of the retroviral oncogene of Moloney murine sarcoma virus and of its cellular homologues. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4198–4201. [PMC free article] [PubMed]
  • Hahn BH, Shaw GM, Taylor ME, Redfield RR, Markham PD, Salahuddin SZ, Wong-Staal F, Gallo RC, Parks ES, Parks WP. Genetic variation in HTLV-III/LAV over time in patients with AIDS or at risk for AIDS. Science. 1986 Jun 20;232(4757):1548–1553. [PubMed]
  • Hahn CS, Rice CM, Strauss EG, Lenches EM, Strauss JH. Sindbis virus ts103 has a mutation in glycoprotein E2 that leads to defective assembly of virions. J Virol. 1989 Aug;63(8):3459–3465. [PMC free article] [PubMed]
  • Holland JJ, de la Torre JC, Steinhauer DA, Clarke D, Duarte E, Domingo E. Virus mutation frequencies can be greatly underestimated by monoclonal antibody neutralization of virions. J Virol. 1989 Dec;63(12):5030–5036. [PMC free article] [PubMed]
  • Holland JJ, Domingo E, de la Torre JC, Steinhauer DA. Mutation frequencies at defined single codon sites in vesicular stomatitis virus and poliovirus can be increased only slightly by chemical mutagenesis. J Virol. 1990 Aug;64(8):3960–3962. [PMC free article] [PubMed]
  • Holland JJ, Grabau EA, Jones CL, Semler BL. Evolution of multiple genome mutations during long-term persistent infection by vesicular stomatitis virus. Cell. 1979 Mar;16(3):495–504. [PubMed]
  • Holland J, Spindler K, Horodyski F, Grabau E, Nichol S, VandePol S. Rapid evolution of RNA genomes. Science. 1982 Mar 26;215(4540):1577–1585. [PubMed]
  • Huovilainen A, Hovi T, Kinnunen L, Takkinen K, Ferguson M, Minor P. Evolution of poliovirus during an outbreak: sequential type 3 poliovirus isolates from several persons show shifts of neutralization determinants. J Gen Virol. 1987 May;68(Pt 5):1373–1378. [PubMed]
  • Jansen RW, Newbold JE, Lemon SM. Complete nucleotide sequence of a cell culture-adapted variant of hepatitis A virus: comparison with wild-type virus with restricted capacity for in vitro replication. Virology. 1988 Apr;163(2):299–307. [PubMed]
  • Kew OM, Nottay BK, Hatch MH, Nakano JH, Obijeski JF. Multiple genetic changes can occur in the oral poliovaccines upon replication in humans. J Gen Virol. 1981 Oct;56(Pt 2):337–347. [PubMed]
  • Kinnunen L, Huovilainen A, Pöyry T, Hovi T. Rapid molecular evolution of wild type 3 poliovirus during infection in individual hosts. J Gen Virol. 1990 Feb;71(Pt 2):317–324. [PubMed]
  • Lande R. Expected time for random genetic drift of a population between stable phenotypic states. Proc Natl Acad Sci U S A. 1985 Nov;82(22):7641–7645. [PMC free article] [PubMed]
  • Lefrancios L, Lyles DS. The interactionof antiody with the major surface glycoprotein of vesicular stomatitis virus. I. Analysis of neutralizing epitopes with monoclonal antibodies. Virology. 1982 Aug;121(1):157–167. [PubMed]
  • Lefrancois L, Lyles DS. The interaction of antibody with the major surface glycoprotein of vesicular stomatitis virus. II. Monoclonal antibodies of nonneutralizing and cross-reactive epitopes of Indiana and New Jersey serotypes. Virology. 1982 Aug;121(1):168–174. [PubMed]
  • Lefrancois L, Lyles DS. Antigenic determinants of vesicular stomatitis virus: analysis with antigenic variants. J Immunol. 1983 Jan;130(1):394–398. [PubMed]
  • Minor PD, John A, Ferguson M, Icenogle JP. Antigenic and molecular evolution of the vaccine strain of type 3 poliovirus during the period of excretion by a primary vaccinee. J Gen Virol. 1986 Apr;67(Pt 4):693–706. [PubMed]
  • Moss EG, O'Neill RE, Racaniello VR. Mapping of attenuating sequences of an avirulent poliovirus type 2 strain. J Virol. 1989 May;63(5):1884–1890. [PMC free article] [PubMed]
  • Mudd JA, Summers DF. Protein synthesis in vesicular stomatitis virus-infected HeLa cells. Virology. 1970 Oct;42(2):328–340. [PubMed]
  • Nichol ST. Genetic diversity of enzootic isolates of vesicular stomatitis virus New Jersey. J Virol. 1988 Feb;62(2):572–579. [PMC free article] [PubMed]
  • Nichol ST, Rowe JE, Fitch WM. Glycoprotein evolution of vesicular stomatitis virus New Jersey. Virology. 1989 Feb;168(2):281–291. [PubMed]
  • O'Hara PJ, Horodyski FM, Nichol ST, Holland JJ. Vesicular stomatitis virus mutants resistant to defective-interfering particles accumulate stable 5'-terminal and fewer 3'-terminal mutations in a stepwise manner. J Virol. 1984 Mar;49(3):793–798. [PMC free article] [PubMed]
  • Omata T, Kohara M, Kuge S, Komatsu T, Abe S, Semler BL, Kameda A, Itoh H, Arita M, Wimmer E, et al. Genetic analysis of the attenuation phenotype of poliovirus type 1. J Virol. 1986 May;58(2):348–358. [PMC free article] [PubMed]
  • Parvin JD, Moscona A, Pan WT, Leider JM, Palese P. Measurement of the mutation rates of animal viruses: influenza A virus and poliovirus type 1. J Virol. 1986 Aug;59(2):377–383. [PMC free article] [PubMed]
  • Pilipenko EV, Blinov VM, Romanova LI, Sinyakov AN, Maslova SV, Agol VI. Conserved structural domains in the 5'-untranslated region of picornaviral genomes: an analysis of the segment controlling translation and neurovirulence. Virology. 1989 Feb;168(2):201–209. [PubMed]
  • Pincus SE, Diamond DC, Emini EA, Wimmer E. Guanidine-selected mutants of poliovirus: mapping of point mutations to polypeptide 2C. J Virol. 1986 Feb;57(2):638–646. [PMC free article] [PubMed]
  • Portner A, Webster RG, Bean WJ. Similar frequencies of antigenic variants in Sendai, vesicular stomatitis, and influenza A viruses. Virology. 1980 Jul 15;104(1):235–238. [PubMed]
  • Preston BD, Poiesz BJ, Loeb LA. Fidelity of HIV-1 reverse transcriptase. Science. 1988 Nov 25;242(4882):1168–1171. [PubMed]
  • Pringle CR. Genetic characteristics of conditional lethal mutants of vesicular stomatitis virus induced by 5-fluorouracil, 5-azacytidine, and ethyl methane sulfonate. J Virol. 1970 May;5(5):559–567. [PMC free article] [PubMed]
  • Roberts JD, Bebenek K, Kunkel TA. The accuracy of reverse transcriptase from HIV-1. Science. 1988 Nov 25;242(4882):1171–1173. [PubMed]
  • Sedivy JM, Capone JP, RajBhandary UL, Sharp PA. An inducible mammalian amber suppressor: propagation of a poliovirus mutant. Cell. 1987 Jul 31;50(3):379–389. [PubMed]
  • Smith DB, Inglis SC. The mutation rate and variability of eukaryotic viruses: an analytical review. J Gen Virol. 1987 Nov;68(Pt 11):2729–2740. [PubMed]
  • Sobrino F, Dávila M, Ortín J, Domingo E. Multiple genetic variants arise in the course of replication of foot-and-mouth disease virus in cell culture. Virology. 1983 Jul 30;128(2):310–318. [PubMed]
  • Spindler KR, Horodyski FM, Holland JJ. High multiplicities of infection favor rapid and random evolution of vesicular stomatitis virus. Virology. 1982 May;119(1):96–108. [PubMed]
  • Steinhauer DA, de la Torre JC, Holland JJ. High nucleotide substitution error frequencies in clonal pools of vesicular stomatitis virus. J Virol. 1989 May;63(5):2063–2071. [PMC free article] [PubMed]
  • Steinhauer DA, de la Torre JC, Meier E, Holland JJ. Extreme heterogeneity in populations of vesicular stomatitis virus. J Virol. 1989 May;63(5):2072–2080. [PMC free article] [PubMed]
  • Steinhauer DA, Holland JJ. Rapid evolution of RNA viruses. Annu Rev Microbiol. 1987;41:409–433. [PubMed]
  • Strauss JH, Strauss EG. Evolution of RNA viruses. Annu Rev Microbiol. 1988;42:657–683. [PubMed]
  • Valcárcel J, Ortín J. Phenotypic hiding: the carryover of mutations in RNA viruses as shown by detection of mar mutants in influenza virus. J Virol. 1989 Sep;63(9):4107–4109. [PMC free article] [PubMed]
  • Vandepol SB, Lefrancois L, Holland JJ. Sequences of the major antibody binding epitopes of the Indiana serotype of vesicular stomatitis virus. Virology. 1986 Jan 30;148(2):312–325. [PubMed]
  • Ward CD, Stokes MA, Flanegan JB. Direct measurement of the poliovirus RNA polymerase error frequency in vitro. J Virol. 1988 Feb;62(2):558–562. [PMC free article] [PubMed]
  • Westrop GD, Wareham KA, Evans DM, Dunn G, Minor PD, Magrath DI, Taffs F, Marsden S, Skinner MA, Schild GC, et al. Genetic basis of attenuation of the Sabin type 3 oral poliovirus vaccine. J Virol. 1989 Mar;63(3):1338–1344. [PMC free article] [PubMed]
  • Wilusz J, Youngner JS, Keene JD. Base mutations in the terminal noncoding regions of the genome of vesicular stomatitis virus isolated from persistent infections of L cells. Virology. 1985 Jan 30;140(2):249–256. [PubMed]

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