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Entry receptors — the gateway to alphavirus infection
Ofer Zimmerman, … , Lucas J. Adams, Michael S. Diamond
Ofer Zimmerman, … , Lucas J. Adams, Michael S. Diamond
Published January 17, 2023
Citation Information: J Clin Invest. 2023;133(2):e165307. https://doi.org/10.1172/JCI165307.
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Review Series

Entry receptors — the gateway to alphavirus infection

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Abstract

Alphaviruses are enveloped, insect-transmitted, positive-sense RNA viruses that infect humans and other animals and cause a range of clinical manifestations, including arthritis, musculoskeletal disease, meningitis, encephalitis, and death. Over the past four years, aided by CRISPR/Cas9–based genetic screening approaches, intensive research efforts have focused on identifying entry receptors for alphaviruses to better understand the basis for cellular and species tropism. Herein, we review approaches to alphavirus receptor identification and how these were used for discovery. The identification of new receptors advances our understanding of viral pathogenesis, tropism, and evolution and is expected to contribute to the development of novel strategies for prevention and treatment of alphavirus infection.

Authors

Ofer Zimmerman, Autumn C. Holmes, Natasha M. Kafai, Lucas J. Adams, Michael S. Diamond

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Figure 1

Alphavirus phylogeny, genome composition, and virion structure.

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Alphavirus phylogeny, genome composition, and virion structure.
(A) Phyl...
(A) Phylogenetic tree constructed from pairwise distances between alphavirus structural protein (E1 and E2) sequences, visualized in R using the ggtree package (179). Viruses include chikungunya (CHIKV, NCBI GenBank: QKY67868.1), Mayaro (MAYV, QED21311.1), Una (UNAV, YP_009665989.1), O’nyong’nyong (ONNV, AAC97205.1), Semliki Forest (SFV, NP_463458.1), Ross River (RRV, AAA47404.1), Eastern equine encephalitis (EEEV, ANB41743.1), Madariaga (MADV, AXV43855.1), Venezuelan equine encephalitis (VEEV, AGE98294.2), Sindbis (SINV, AAM10630.1), Aura (AURV, NP_632024.1), Ockelbo (OCKV, P27285.1), Western equine encephalitis (WEEV, QEX51909.1), Buggy Creek (BCV, AEJ36227.1), Babanki (BBKV, AVN98166.1), Fort Morgan (FMV, YP_003324588.1), Highlands J (HJV, YP_002802300.1), and Whataroa (WHAV, AEJ36239.1) viruses. Viruses with known receptors are in shaded bubbles. (B) The alphavirus genome consists of two open reading frames, a 49S genomic RNA encoding both nonstructural and structural proteins, and 26S subgenomic RNA encoding only the structural proteins. (C) Cryo–electron microscopy reconstruction of VEEV virus-like particle (EMD-24117) (167) colored radially, with an equatorial cross section shown as a round inset. Axes of symmetry are designated by a pentagon (5-fold; i5), triangles (3-fold; i3), three-pointed stars (quasi-3-fold; q3), and a diamond (2-fold; i2), with axial orientations displayed in the inset. (D) Model of VEEV structural proteins (Protein Data Bank 7FFE), including E3, which is cleaved during viral maturation, colored by domain as indicated. Cryo–electron microscopy map and model visualized using ChimeraX (180). FL, fusion loop; TM, transmembrane. Panels C and D use structural data from Basore et al. (165) and Ma et al. (168).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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