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The Alphaviruses: Gene Expression, Replication, and Evolution JAMES H

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The Alphaviruses: Gene Expression, Replication, and Evolution JAMES H MICROBIOLOGICAL REVIEWS, Sept. 1994, p. 491-562 Vol. 58, No. 3 0146-0749/94/$04.00+0 Copyright C) 1994, American Society for Microbiology The Alphaviruses: Gene Expression, Replication, and Evolution JAMES H. STRAUSS* AND ELLEN G. STRAUSS Division of Biology, Califomia Institute of Technology, Pasadena, Califomia 91125 INTRODUCTION ................................................... 492 The Cast of Characters ................................................... 492 Dispersal of Alphaviruses................................................... 494 Full-Length Clones of Alphaviruses................................................... 494 STRUCTURE OF ALPHAVIRUSES ................................................... 495 Structure of the Virion................................................... 495 Nucleocapsid................................................... 495 Virion envelope................................................... 496 Organization of the Alphavirus Genome................................................... 498 REPLICATION OF ALPHAVIRUSES................................................... 499 Overview of the Alphavirus Life Cycle................................................... 499 Structural Proteins ................................................... 499 Capsid protein................................................... 499 Synthesis of glycoproteins................................................... 500 Addition of carbohydrate and lipids ................................................... 502 Folding and transport of glycoproteins ................................................... 502 Cleavage of PE2 during transport................................................... 503 Reorientation of the E2 C-terminal domain ................................................... 504 Virus Assembly................................................... 505 Assembly of nucleocapsids................................................... 505 Capsid-spike interaction during budding................................................... 506 Domains involved in the E2-nucleocapsid interaction ................................................... 506 Lateral interactions between glycoproteins ................................................... 508 The 6K protein and ion gradients in assembly................................................... 509 Nonstructural Proteins ................................................... 509 Translation..........................509 Functions ofnsPi....................................................510 Functions of nsP2 ................................................... 510 Functions of nsP3 ................................................... 511 Functions of nsP4 ................................................... 511 Nonstructural Proteinase................................................... 512 Active site of the enzyme................................................... 512 Nature of cleavage sites recognized by the enzyme................................................... 512 Cleavage site preferences of the enzyme................................................... 513 Synthesis of Viral RNAs ................................................... 514 RNA replicase................................................... 514 Control of minus-strand RNA synthesis ................................................... 514 Role of the opal termination codon................................................... 517 cis-ACTING SEQUENCE ELEMENTS IN ALPHAVIRUS RNAS ................................................... 518 Conserved Nucleotide Sequence Elements ................................................... 518 Identification of CSEs ................................................... 518 Mutagenesis of CSEs................................................... 519 CSEs can be tissue specific ................................................... 519 Cellular proteins bind to CSEs................................................... 519 Promoter for subgenomic RNA synthesis................................................... 520 Repeated Sequence Elements in the 3' NTR................................................... 521 Sequences in DI RNAs Define Essential cis-Acting Elements................................................... 522 Packaging Signal in Alphavirus RNAs ................................................... 524 Chimeric Alphaviruses ................................................... 525 Alphaviruses as Vectors ................................................... 525 VIRUS-HOST INTERACTIONS................................................... 526 Host Cell Receptors for Alphaviruses................................................... 526 Early studies of alphavirus receptors ................................................... 527 Anti-idiotypic antibodies as antireceptor antibodies ................................................... 527 * Corresponding author. Phone: (818) 395-4903. Fax: (818) 449- 0756. Electronic mail address: [email protected]. 491 492 STRAUSS AND STRAUSS MICROBIOL. REV. Laminin receptor as a mammalian receptor ..528 Mosquito receptor for VEE .................... ..529 Virus receptor-binding domain.......................*....................................................................................cln.hY! Virus Entry............................................................ ..530 Early events in virus penetration................... ..530 Entry into endosomes....................................... .................*.................................................................................531 Conformational changes in El and E2.......... ..532 Cholesterol requirement for entry by SF....... ..533 Early Events in Establishment of Infection.................................................................. 6........0....0.........................533 Nucleocansdl dlsassembIv.3s.............................................................................. .. .. .. Superinfection exclusion.................................... Inhibition of host protein synthesis................. ..534 Formation of replication factories.............................................................................................6.........................535 Pathogenesis and Immunity.................................. ..536 Neutralization epitopes in E2........................... ..536 Neutralization epitopes in El........................... ..536 Conformational dependence of epitopes.......... ..536 Protection from disease................................................................................................ oeo ......................................537 Virus neurovirulence............................... I... oo..O..Oo ................................... 0-0.0 .00-0.0000.0 ...............I..537 Clearance of virus from persistently infected neurons...... .539 Induction of apoptosis........................................I.................................................................................................539 Replication in the Mosquito Vector..................... .540 EVOLUTION OF ALPHAVIRUSES........................I...........................................0....................... *..* ..........................541 Divergence of Alphaviruses ................................... .541 e' A II Rates of divergence...............................................................................................................................................541 Divergence of EEE and VEE............................. Divergence of Sindbis viruses........................... .543 Alphavirus evolutionary trees........................... .543 Recombination among Alphaviruses................... I................................................................................................,.544 Recombination in the laboratory..................... .544 Recombination to form WEE........................... caA The Family Togaviridae.......................................... The Sindbis-Like Supergroup of Viruses . .545 CONCLUDING REMARKS. .546 ACKNOWVLEDGMENTS ...................................... pA'7 REFERENCES ...................................... INTRODUCTION isolated from New Zealand (WHA) (484) and from South American (AURA) (434). The relationship of OCK to SIN The Cast of Characters deserves special mention. OCK has often been described as a The alphaviruses have 26 currently recognized members distinct species because it causes a human disease different (55). Each virus in turn consists of numerous geographical from that caused by SIN and it is serologically distinguishable variants or strains. Inclusion in the genus Alphavirus has been from SIN. However, OCK is much more closely related to SIN based on serological cross-reaction with one or more of the AR339 and to South African strains of SIN than are strains existing members of the group (55, 409). Complete or partial called SIN that have been isolated from India, the Philippines, sequences of the RNA genomes of more than 10 alphaviruses or Australia. In this review we will refer to OCK as a strain of have now been reported, and these alphaviruses all share a SIN, on the basis of close sequence relationships, and use the minimum amino acid sequence identity of about 45% in the term SIN-like viruses to include WHA and AURA. more divergent structural proteins and about 60% in the Other Old World alphaviruses have more restricted distri- nonstructural proteins. Table 1 lists the currently recognized butions. RR, for example, is primarily an Australian
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