Autor(es): Silva Laurie A, Khom-iak Solomiia, Ashbrook Alison W, Weller Romy, Heise Mark T, Morrison Thomas E, Dermody Terence S

Resumo: Chikungunya virus (CHIKV) is a reemerging arbovirus responsible for outbreaks of infection throughout Asia - Africa, causing an acute illness characterized by fever, rash, - polyarthralgia. Although CHIKV infects a broad range of host cells, little is known about how CHIKV binds - gains access to the target cell interior. In this study, we tested whether glycosaminoglycan (GAG) binding is required for efficient CHIKV replication using CHIKV vaccine strain 181/25 - clinical isolate SL15649. Preincubation of strain 181/25, but not SL15649, with soluble GAGs resulted in dose-dependent inhibition of infection. While parental Chinese hamster ovary (CHO) cells are permissive for both strains, neither strain efficiently bound to or infected mutant CHO cells devoid of GAG expression. Although GAGs appear to be required for efficient binding of both strains, they exhibit differential requirements for GAGs, as SL15649 readily infected cells that express excess chondroitin sulfate but that are devoid of heparan sulfate, whereas 181/25 did not. We generated a panel of 181/25 - SL15649 variants containing reciprocal amino acid substitutions at positions 82 - 318 in the E2 glycoprotein. Reciprocal exchange at residue 82 resulted in a phenotype switch; Gly(82) results in efficient infection of mutant CHO cells but a decrease in heparin binding, whereas Arg(82) results in reduced infectivity of mutant cells - an increase in heparin binding. These results suggest that E2 residue 82 is a primary determinant of GAG utilization, which likely mediates attenuation of vaccine strain 181/25. Chikungunya virus (CHIKV) infection causes a debilitating rheumatic disease that can persist for months to years, - yet there are no licensed vaccines or antiviral therapies. Like other alphaviruses, CHIKV displays broad tissue tropism, which is thought to be influenced by virus-receptor interactions. In this study, we determined that cell-surface glycosaminoglycans are utilized by both a vaccine strain - a clinical isolate of CHIKV to mediate virus binding. We also identified an amino acid polymorphism in the viral E2 attachment protein that influences utilization of glycosaminoglycans. These data enhance an underst-ing of the viral - host determinants of CHIKV cell entry, which may foster development of new antivirals that act by blocking this key step in viral infection.

Imprenta: Journal of Virology, v. 88, n. 5, p. 2385-2397, 2014

Identificador do objeto digital: 10.1128/JVI.03116-13

Descritores: Chikungunya virus - Arbovirus ; Chikungunya virus - Biosynthesis ; Chikungunya virus - Cell ; Chikungunya virus - Pathogenesis ; Chikungunya virus - Proteins ; Chikungunya virus - Viral infections ; Chikungunya Virus - Virus ; Chikungunya virus - Vaccine ; Chikungunya virus - Chikungunya fever

Data de publicação: 2014