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

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 2

Alphavirus infection cycle.

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Alphavirus infection cycle. Alphaviruses can engage attachment factors (...
Alphaviruses can engage attachment factors (e.g., HS) and specific receptors (e.g., MXRA8, LDLRAD3, VLDLR, and ApoER2) at the cell surface to mediate binding and entry. Virions enter cells principally through endocytosis of clathrin-coated vesicles. The acidic environment of the transiting endosome triggers conformational changes in the envelope proteins, allowing for fusion with endosomal membranes, penetration into the cytoplasm where nucleocapsid disassembly occurs, and translation of the incoming positive-strand genomic RNA. At early stages of infection, genomic RNA is translated to yield P123 and P1234 polyproteins (52). P1234 is cleaved in cis by the nsP2 protease to generate the viral proteins necessary for transcription and replication (53, 54). The early replicase, P123 and nsP4, is processed into a short-lived nsP1, P23, and nsP4 complex and, further, into a late replicase consisting of nsP1, nsP2, nsP3, and nsP4. The early replicase synthesizes negative-strand RNA, which is used for production of genomic and subgenomic RNAs (26S) (55–58). The subgenomic mRNA drives expression of structural polyproteins C-pE2-6K/TF-E1 (56, 57). The E2 envelope glycoprotein is translated and covalently linked to E3 to form the polyprotein pE2, which associates with E1. The transframe (TF) protein is produced by ribosomal frameshift during translation of the 6K gene. The viral capsid (C) protein is released by its autoprotease activity and associates with newly synthesized genomic RNA to form the nucleocapsid. The remaining structural polyprotein is processed and matured in the endoplasmic reticulum, where host signal peptidases cleave pE2, 6K/TF, and E1 (63, 68, 70–72). Furin-like proteases (FLP) in the Golgi network cleave pE2 into the component envelope glycoproteins E2 and E3 (for some alphaviruses, i.e., SINV, SFV, and VEEV, E3 may remain associated with the virion) (73–76). Mature E2-E1 glycoproteins are transported to the plasma membrane where nucleocapsid associates to trigger budding and egress of mature virions (80–86).