RESUMO
Dengue virus (DENV) is a flavivirus responsible for the most common and burdensome arthropod-borne viral disease of humans[1]. DENV evolution has been extensively studied on broad geographic and time scales, using sequences from a single gene[2,3]. It is believed that DENV evolution in humans is dominated primarily by purifying selection due to the constraint of maintaining fitness in both humans and mosquitoes[4,5]. Few studies have explored DENV evolutionary dynamics using whole genome sequences, nor have they explored changes in viral diversity that occur during intra-epidemic periods. We used deep sequencing of the viral coding region to characterize DENV-1 evolution in a Colombian population sampled during two high-prevalence dengue seasons in which serotype dominance shifted. Our data demonstrate patterns of strain extinction and replacement within DENV-1 as its prevalence waned and DENV-3 became established. A comparison of whole-genome versus single-gene-based phylogenetic analyses highlights an important difference in evolutionary patterns. We report a trend of higher nonsynonymous to synonymous diversity ratios among non-structural (NS) genes, and statistically significantly higher values among these ratios in the NS1 gene after DENV-1 strain replacement. These results suggest that positive selection could be driving DENV evolution within individual communities. Signals of positive selection coming from distinct samples may be drowned out when combining multiple regions with differing patterns of endemic transmission as commonly done by large-scale geo-temporal assessments. Here, we frame our findings within a small, local transmission history which aids significance. Moreover, these data suggest that the NS1 gene, rather than the E gene, may be a target of positive selection, although not mutually exclusive, and potentially useful sentinel of adaptive changes at the population level.
Assuntos
Vírus da Dengue/genética , Dengue/virologia , Doenças Endêmicas , Evolução Molecular , Proteínas não Estruturais Virais/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Colômbia/epidemiologia , Dengue/epidemiologia , Dengue/transmissão , Feminino , Variação Genética , Genoma Viral , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , Prevalência , RNA Viral/isolamento & purificação , Seleção Genética , Sorogrupo , Proteínas do Envelope Viral/genética , Sequenciamento Completo do Genoma , Adulto JovemRESUMO
Mosquito-borne Zika virus (ZIKV) typically causes a mild and self-limiting illness known as Zika fever. Since its recent emergence in 2014 in the American continent, ZIKV infection during pregnancy has been closely associated with a wide range of congenital abnormalities. To date, no vaccines or antivirals are publicly available. We developed Zika virus-like particles (VLPs) and evaluated their immunogenicity and protective efficacy in mouse models. ZIKV VLPs (ZIKVLPs) formulated with alum were injected into 6-8-week-old interferon deficient AG129 mice as well as wild type BALB/c mice. Control mice received PBS/alum. Animals were challenged with 200 PFU (>1000 AG129 LD50s) of ZIKV strain H/PF/2013. All vaccinated mice survived with no morbidity or weight loss while control animals either died at 9 days post challenge (AG129) or had increased viremia (BALB/c). Neutralizing antibodies were observed in all ZIKVLP vaccinated mice. The role of neutralizing antibodies in protecting mice was demonstrated by passive transfer. Our findings demonstrate the protective efficacy of the ZIKVLP vaccine and highlight the important role that neutralizing antibodies play in protection against ZIKV infection.
