Understanding the alphaviruses: recent research on important emerging pathogens and progress towards their control

Abstract

The alphaviruses were amongst the first arboviruses to be isolated, characterized and assigned a taxonomic status. They are globally very widespread, infecting a large variety of terrestrial animals, insects and even fish, and circulate both in the sylvatic and urban/peri-urban environment, causing considerable human morbidity and mortality. Nevertheless, despite their obvious importance as pathogens, there are currently no effective antiviral drugs with which to treat humans or animals infected by any of these viruses. The EU-supported project-VIZIER (Comparative Structural Genomics of Viral Enzymes Involved in Replication, FP6 PROJECT: 2004-511960) was instigated with an ultimate view of contributing to the development of antiviral therapies for RNA viruses, including the alphaviruses [Coutard, B., Gorbalenya, A.E., Snijder, E.J., Leontovich, A.M., Poupon, A., De Lamballerie, X., Charrel, R., Gould, E.A., Gunther, S., Norder, H., Klempa, B., Bourhy, H., Rohayemj, J., L'hermite, E., Nordlund, P., Stuart, D.I., Owens, R.J., Grimes, J.M., Tuckerm, P.A., Bolognesi, M., Mattevi, A., Coll, M., Jones, T.A., Aqvist, J., Unger, T., Hilgenfeld, R., Bricogne, G., Neyts, J., La Colla, P., Puerstinger, G., Gonzalez, J.P., Leroy, E., Cambillau, C., Romette, J.L., Canard, B., 2008. The VIZIER project: preparedness against pathogenic RNA viruses. Antiviral Res. 78, 37-46]. This review highlights some of the major features of alphaviruses that have been investigated during recent years. After describing their classification, epidemiology and evolutionary history and the expanding geographic distribution of Chikungunya virus, we review progress in understanding the structure and function of alphavirus replicative enzymes achieved under the VIZIER programme and the development of new disease control strategies.

Fig. 1

Alphavirus genome coding strategy (adapted and updated from Strauss and Strauss, 1994). Open-reading frame (ORF) represented as open box, and untranslated regions as solid black lines; sg (subgenomic), asterisk between nsP3 and nsP4 identifies the position of the stop codon that is present in some alphaviruses and is read through to produce the precursor nsP1,2,3,4 polyprotein, Me-tr (methyltransferase), Hel (helicase), Pro (protease), MD (macro domain—exhibits adenosine di-phosphoribose 1″-phosphate phosphatase activity), RdRp (RNA-dependent RNA polymerase), C (capsid), E (envelope).

Fig. 2

Phylogenetic analyses of selected alphaviruses. (a) Midpoint rooted tree generated using partial E1 envelope glycoprotein amino acid sequences and the neighbour joining program implemented in PAUP 4.0 (Swofford, 1998). Numbers indicate bootstrap values generated using 1000 resamplings. Scale indicates 5% amino acid sequence divergence. Gray box shows recombinant alphaviruses that were derived from ancestors of EEEV and SINV. Shaded background indicates recombinant viruses. (b) Most parsimonious alphavirus nsP4 tree, rooted with NSA/SPDV outgroup Bootstrap percentage numbers on nodes with 50% or more support from 1000 resamplings, are indicated. Asterisk (*) indicates studies in VIZIER; shaded background indicates New World viruses.

Fig. 3

Known structures of alphavirus nsP2 (protease) and nsP3 (macro domain). (a) Cartoon representation of the VEEV protease (C-terminal part of nsP2) (Russo et al., 2006). The domain coloured in orange corresponds to the catalytic domain where the catalytic cysteine and histidine are highlighted respectively in yellow and red. (b) Cartoon representation of the CHIKV macro domain (in green) complex with ADP-ribose (in blue). (c) Cartoon representation of the VEEV macro domain (in pink) complex with ADP-ribose (in yellow) (Malet et al., 2009).