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Yellow fever virus exhibits slower evolutionary dynamics than dengue virus.

ABSTRACT: Although yellow fever has historically been one of the most important viral infections of humans, relatively little is known about the evolutionary processes that shape its genetic diversity. Similarly, there is limited information on the molecular epidemiology of yellow fever virus (YFV) in Africa even though it most likely first emerged on this continent. Through an analysis of complete E gene sequences, including a newly acquired viral collection from Central and West Africa (Senegal, Cameroon, Central African Republic, Côte d'Ivoire, Mali, and Mauritania), we show that YFV exhibits markedly lower rates of evolutionary change than dengue virus, despite numerous biological similarities between these two viruses. From this observation, along with a lack of clock-like evolutionary behavior in YFV, we suggest that vertical transmission, itself characterized by lower replication rates, may play an important role in the evolution of YFV in its enzootic setting. Despite a reduced rate of nucleotide substitution, phylogenetic patterns and estimates of times to common ancestry in YFV still accord well with the dual histories of colonialism and the slave trade, with areas of sylvatic transmission (such as Kedougou, Senegal) acting as enzootic/epidemic foci.

SUBMITTER: Sall AA

PROVIDER: S-EPMC2798388 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Yellow fever virus exhibits slower evolutionary dynamics than dengue virus.

Sall Amadou A AA Faye Ousmane O Diallo Mawlouth M Firth Cadhla C Kitchen Andrew A Holmes Edward C EC

Journal of virology 20091104 2

Although yellow fever has historically been one of the most important viral infections of humans, relatively little is known about the evolutionary processes that shape its genetic diversity. Similarly, there is limited information on the molecular epidemiology of yellow fever virus (YFV) in Africa even though it most likely first emerged on this continent. Through an analysis of complete E gene sequences, including a newly acquired viral collection from Central and West Africa (Senegal, Cameroo ...[more]

PMID: 19889759

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Project description:Two yellow fever virus (YFV)/dengue virus chimeras which encode the prM and E proteins of either dengue virus serotype 2 (dengue-2 virus) or dengue-4 virus within the genome of the YFV 17D strain (YF5.2iv infectious clone) were constructed and characterized for their properties in cell culture and as experimental vaccines in mice. The prM and E proteins appeared to be properly processed and glycosylated, and in plaque reduction neutralization tests and other assays of antigenic specificity, the E proteins exhibited profiles which resembled those of the homologous dengue virus serotypes. Both chimeric viruses replicated in cell lines of vertebrate and mosquito origin to levels comparable to those of homologous dengue viruses but less efficiently than the YF5.2iv parent. YFV/dengue-4 virus, but not YFV/dengue-2 virus, was neurovirulent for 3-week-old mice by intracerebral inoculation; however, both viruses were attenuated when administered by the intraperitoneal route in mice of that age. Single-dose inoculation of either chimeric virus at a dose of 10(5) PFU by the intraperitoneal route induced detectable levels of neutralizing antibodies against the homologous dengue virus strains. Mice which had been immunized in this manner were fully protected from challenge with homologous neurovirulent dengue viruses by intracerebral inoculation compared to unimmunized mice. Protection was associated with significant increases in geometric mean titers of neutralizing antibody compared to those for unimmunized mice. These data indicate that YFV/dengue virus chimeras elicit antibodies which represent protective memory responses in the mouse model of dengue encephalitis. The levels of neurovirulence and immunogenicity of the chimeric viruses in mice correlate with the degree of adaptation of the dengue virus strain to mice. This study supports ongoing investigations concerning the use of this technology for development of a live attenuated viral vaccine against dengue viruses.

Project description:A chimeric yellow fever (YF)-dengue type 2 (dengue-2) virus (ChimeriVax-D2) was constructed using a recombinant cDNA infectious clone of a YF vaccine strain (YF 17D) as a backbone into which we inserted the premembrane (prM) and envelope (E) genes of dengue-2 virus (strain PUO-218 from a case of dengue fever in Bangkok, Thailand). The chimeric virus was recovered from the supernatant of Vero cells transfected with RNA transcripts and amplified once in these cells to yield a titer of 6.3 log(10) PFU/ml. The ChimeriVax-D2 was not neurovirulent for 4-week-old outbred mice inoculated intracerebrally. This virus was evaluated in rhesus monkeys for its safety (induction of viremia) and protective efficacy (induction of anti-dengue-2 neutralizing antibodies and protection against challenge). In one experiment, groups of non-YF-immune monkeys received graded doses of ChimeriVax-D2; a control group received only the vaccine diluents. All monkeys (except the control group) developed a brief viremia and showed no signs of illness. Sixty-two days postimmunization, animals were challenged with 5.0 log(10) focus forming units (FFU) of a wild-type dengue-2 virus. No viremia (<1.7 log(10) FFU/ml) was detected in any vaccinated group, whereas all animals in the placebo control group developed viremia. All vaccinated monkeys developed neutralizing antibodies in a dose-dependent response. In another experiment, viremia and production of neutralizing antibodies were determined in YF-immune monkeys that received either ChimeriVax-D2 or a wild-type dengue-2 virus. Low viremia was detected in ChimeriVax-D2-inoculated monkeys, whereas all dengue-2-immunized animals became viremic. All of these animals were protected against challenge with a wild-type dengue-2 virus, whereas all YF-immune monkeys and nonimmune controls became viremic upon challenge. Genetic stability of ChimeriVax-D2 was assessed by continuous in vitro passage in VeroPM cells. The titer of ChimeriVax-D2, the attenuated phenotype for 4-week-old mice, and the sequence of the inserted prME genes were unchanged after 18 passages in Vero cells. The high replication efficiency, attenuation phenotype in mice and monkeys, immunogenicity and protective efficacy, and genomic stability of ChimeriVax-D2 justify it as a novel vaccine candidate to be evaluated in humans.

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Yellow fever virus exhibits slower evolutionary dynamics than dengue virus.

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Yellow fever virus exhibits slower evolutionary dynamics than dengue virus.

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