Very Rapid Generation/Amplification of Defective Interfering Particles by Vesicular Stomatitis Virus Variants Isolated from Persistent Infection

DePolo, Nicholas J.; Holland, John J.

doi:10.1099/0022-1317-67-6-1195

Cited by 18 publications

(12 citation statements)

References 28 publications

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“…The same competition at an MOI of 10 would require more than 40 passages until extinction is reached. Unfortunately, repeated passages at a high MOI cannot be carried out for long periods of time with VSV, since defective interfering particles are expected to accumulate and will act as an additional selective force (6,7). Interestingly, a reduction in the fixation rate of advantageous mutations similar to that caused by complementation is expected from clonal interference (16), even though the underlying biological mechanisms are completely unrelated.…”

Section: Discussionmentioning

confidence: 99%

“…The choice of this time was based on growth curves, and its relationship with 24-h competitions is consistent with titers and with the behavior of fitness changes for this pair of competitors (47). All fitness assays were limited to a single competition passage, to avoid accumulation of defective interfering particles in infections at a high MOI (6,7). In order to get an accurate determination of wt/MARM N ratios, titrations were done with T25 flasks by triplicate plaque assay in the presence and absence of MAb I1.…”

Section: Cells and Virusesmentioning

confidence: 99%

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Density-Dependent Selection in Vesicular Stomatitis Virus

Novella

Reissig

Wilke

2004

J Virol

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We used vesicular stomatitis virus to test the effect of complementation on the relative fitness of a deleterious mutant, monoclonal antibody-resistant mutant (MARM) N, in competition with its wild-type ancestor. We carried out competitions of MARM N and wild-type populations at different multiplicities of infection (MOIs) and initial ratios of the wild type to the mutant and found that the fitness of MARM N relative to that of the wild type is very sensitive to changes in the MOI (i.e., the degree of complementation) but depends little, if at all, on the initial frequencies of MARM N and the wild type. Further, we developed a mathematical model under the assumption that during coinfection both viruses contribute to a common pool of protein products in the infected cell and that they both exploit this common pool equally. Under such conditions, the fitness of all virions that coinfect a cell is the average fitness in the absence of coinfection of that group of virions. In the absence of coinfection, complementation cannot take place and the relative fitness of each competitor is only determined by the selective value of its own products. We found good agreement between our experimental results and the model predictions, which suggests that the wild type and MARM N freely share all of their gene products under coinfection.RNA viruses form highly polymorphic populations called quasispecies (8,9,13). The origin of much of their genetic diversity is high mutational pressure. Most RNA viruses have mutation rates on the order of one miscopied base per genome and generation (10, 11). However, high mutational pressure is not necessarily the only factor promoting genetic diversity. Niche differentiation can allow stable polymorphisms in an infected host. For instance, during a polyclonal immune response, different subpopulations may have different sensitivities to individual antibodies; variation within a host can also be related to differences in the tropism of different viral subpopulations. Virus-virus interactions may also promote stable polymorphisms in an infected host. In cell culture, such interactions readily occur during replication inside a cell and are likely to be an important contributor to the maintenance of variation. When two or more virions coinfect the same cell, complementation can take place. Not every function can be complemented in trans. In positive-stranded viruses, translation and replication are coupled (25); therefore, many functions need to be provided in cis and cannot be rescued by complementation (33, 37). Other proteins can freely interact with heterologous genomes or replicons, even from different viral species (18,21). In the absence of compartmentalization or other limitations to the diffusion of viral products, soluble proteins can interact with any genome inside the cell, potentially changing the phenotype of the virions and masking targets for natural selection to operate. A remarkable example of this phenomenon is phenotypic mixing and hiding, particularly for monoclonal antibody (...

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Section: Discussionmentioning

confidence: 99%

Section: Cells and Virusesmentioning

confidence: 99%

Density-Dependent Selection in Vesicular Stomatitis Virus

Novella

Reissig

Wilke

2004

J Virol

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“…The mechanism by which long-term picornavirus persistence occurs in the presence of an intact immune system remains unclear. It has been shown that DI virus populations, described for many virus families (28,30,98,99) can persist for long periods of time in cell cultures. Spontaneously occurring picornavirus DI populations from cell culture systems demonstrate variously sized deletions in the capsid protein (P1) coding region of the viral genome (57), although defective viruses in foot-and-mouth disease have been shown to have deletions in the leader protein-encoding region (37).…”

Section: Discussionmentioning

confidence: 99%

5′-Terminal Deletions Occur in Coxsackievirus B3 during Replication in Murine Hearts and Cardiac Myocyte Cultures and Correlate with Encapsidation of Negative-Strand Viral RNA

Kim

Tracy

Tapprich

et al. 2005

J Virol

143

251

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Adult human enteroviral heart disease is often associated with the detection of enteroviral RNA in cardiac muscle tissue in the absence of infectious virus. Passage of coxsackievirus B3 (CVB3) in adult murine cardiomyocytes produced CVB3 that was noncytolytic in HeLa cells. Detectable but noncytopathic CVB3 was also isolated from hearts of mice inoculated with CVB3. Sequence analysis revealed five classes of CVB3 genomes with 5 termini containing 7, 12, 17, 30, and 49 nucleotide deletions. Structural changes (assayed by chemical modification) in cloned, terminally deleted 5-nontranslated regions were confined to the cloverleaf domain and localized within the region of the deletion, leaving key functional elements of the RNA intact. Transfection of CVB3 cDNA clones with the 5-terminal deletions into HeLa cells generated noncytolytic virus (CVB3/TD) which was neutralized by anti-CVB3 serum. Encapsidated negative-strand viral RNA was detected using CsCl-purified CVB3/TD virions, although no negative-strand virion RNA was detected in similarly treated parental CVB3 virions. The viral protein VPg was detected on CVB3/TD virion RNA molecules which terminate in 5 CG or 5 AG. Detection of viral RNA in mouse hearts from 1 week to over 5 months postinoculation with CVB3/TD demonstrated that CVB3/TD virus strains replicate and persist in vivo. These studies describe a naturally occurring genomic alteration to an enteroviral genome associated with long-term viral persistence.The six serotypes of the group B coxsackieviruses (CVB1-6) are enteroviruses (Picornaviridae, species HEV-B) (53). The CVB genome is a single-stranded RNA molecule, 7,400 nucleotides (nt) in length, that is encapsidated within an icosahedral shell (74). The 11 viral proteins (83) are encoded by a single open reading frame which is flanked on the 5Ј and 3Ј termini by nontranslated regions (NTRs) (20). The CVB induce numerous human illnesses, including inflammatory heart disease, pancreatitis, and aseptic meningitis and may also trigger the onset of type 1 diabetes (5,31,72,81,82). The CVB were recognized as causes of human heart disease shortly after their description early in the 1950s (26, 27) and remain the enteroviruses most commonly associated with human cardiomyopathies on the grounds of isolation and serology (5,6,34,62,88). Meta-analysis shows an association between enteroviruses and myocarditis in 23% of cases (7), although this association is more variable in cases of dilated cardiomyopathy, a serious disease that often leads to a failing heart (61). Mouse models of CVB-induced pancreatitis (94, 110), myocarditis (45,52,110), myositis (104, 105), and rapid-onset type 1 diabetes (31) which facilitate the study of these diseases have been developed.Enterovirus infections are generally considered to be acute events, with symptoms and virus titers peaking within a few days postinoculation (p.i.) and with virus being cleared by the adaptive immune response (17). However, enterovirus infections can persist under conditions of immunodeficiency (48,51,...

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“…However, they can be replicated and encapsidated by the proteins translated from a helper virus coinfecting the same cell. The mechanisms ensuring the survival and persistence of DIPs are not entirely clear, as they behave as hyperparasites and usually get involve in an arms race with the full virus [33][34][35]. It is possible that the emergence of genomes shortened by deletions might confer an advantage in terms of replication speed compared with the full virus [22].…”

Section: Introductionmentioning

confidence: 99%

“…It is possible that the emergence of genomes shortened by deletions might confer an advantage in terms of replication speed compared with the full virus [22]. Furthermore, there is also evidence of a stronger form of interference whereby the DIPs genome competes more successfully for the viral replicative machinery [34,36].…”

Section: Introductionmentioning

confidence: 99%