Scientific Publications

A phylogenetic analysis using full-length viral genomes of South American dengue serotype 3 in consecutive Venezuelan outbreaks reveals a novel NS5 mutation.

Publication TypeJournal Article
AuthorsSchmidt, DJ, Pickett BE, Camacho D., Comach G., Xhaja K., Lennon NJ, Rizzolo K., de Bosch N., Becerra A., Nogueira ML, Mondini A., da Silva EV, Vasconcelos PF, Muñoz-Jordán JL, Santiago GA, Ocazionez R., Gehrke L., Lefkowitz EJ, Birren BW, Henn MR, and Bosch I.
AbstractDengue virus currently causes 50-100million infections annually. Comprehensive knowledge about the evolution of Dengue in response to selection pressure is currently unavailable, but would greatly enhance vaccine design efforts. In the current study, we sequenced 187 new dengue virus serotype 3 (DENV-3) genotype III whole genomes isolated from Asia and the Americas. We analyzed them together with previously-sequenced isolates to gain a more detailed understanding of the evolutionary adaptations existing in this prevalent American serotype. In order to analyze the phylogenetic dynamics of DENV-3 during outbreak periods; we incorporated datasets of 48 and 11 sequences spanning two major outbreaks in Venezuela during 2001 and 2007-2008, respectively. Our phylogenetic analysis of newly sequenced viruses shows that subsets of genomes cluster primarily by geographic location, and secondarily by time of virus isolation. DENV-3 genotype III sequences from Asia are significantly divergent from those from the Americas due to their geographical separation and subsequent speciation. We measured amino acid variation for the E protein by calculating the Shannon entropy at each position between Asian and American genomes. We found a cluster of seven amino acid substitutions having high variability within E protein domain III, which has previously been implicated in serotype-specific neutralization escape mutants. No novel mutations were found in the E protein of sequences isolated during either Venezuelan outbreak. Shannon entropy analysis of the NS5 polymerase mature protein revealed that a G374E mutation, in a region that contributes to interferon resistance in other flaviviruses by interfering with JAK-STAT signaling was present in both the Asian and American sequences from the 2007-2008 Venezuelan outbreak, but was absent in the sequences from the 2001 Venezuelan outbreak. In addition to E, several NS5 amino acid changes were unique to the 2007-2008 epidemic in Venezuela and may give additional insight into the adaptive response of DENV-3 at the population level.
Year of Publication2011
JournalInfection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases
Volume11
Issue8
Pages2011-9
Date Published (YYYY/MM/DD)2011/12/01
ISSN Number1567-1348
DOI10.1016/j.meegid.2011.09.010
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/21964598?dopt=Abstract