Insight into the Life Cycle of Enterovirus-A71

Abstract

Human enterovirus 71 (EV-A71), a member of the Picornaviridae family, is predominantly associated with hand, foot, and mouth disease in infants and young children. Additionally, EV-A71 can cause severe neurological complications, including aseptic meningitis, brainstem encephalitis, and fatalities. The molecular mechanisms underlying these symptoms are complex and involve the viral tissue tropism, evasion from the host immune responses, induction of the programmed cell death, and cytokine storms. This review article delves into the EV-A71 life cycle, with a particular emphasis on recent advancements in understanding the virion structure, tissue tropism, and the interplay between the virus and host regulatory networks during replication. The comprehensive review is expected to contribute to our understanding of EV-A71 pathogenesis and inform the development of antiviral therapies and vaccines.

Keywords: enterovirus 71; life cycle; virus–host interaction.

Figure 1

Overview of the EV-A71 virion structure and its life cycle. (A) EV-A71 virion showing the pentamer (purple line), the different symmetry axes (red point), and the location of the canyon (green circle). Twelve pentamers constitute the icosahedral capsid. (B) The protomer, delineated by a red line, is composed of the viral proteins VP1, VP2, VP3, and the internal VP4, with five protomers assembling into a pentameric structure. (C) A summary of the EV-A71 life cycle. After binding to some specific receptors and internalization, the virion releases its genomic RNA across the endosomal membrane into the cytoplasm, facilitated by the uncoating receptor and low pH. Translation of the genome results in the polyprotein that is subsequently cleaved into structural proteins (VP0, VP1, VP3) and nonstructural proteins (2A–2C and 3A–3D). For genome replication, replication organelles are derived from the Golgi apparatus and lipid droplets. The replication process, catalyzed by the 3D^pol enzyme, begins with the synthesis of a minus RNA strand, which serves as a template for the production of new positive RNA strands. These +RNA strands can either re-enter the replication cycle or be encapsidated into the capsids to form progeny virions. After the cleavage of VP0 into VP2 and VP4, the subsequent release of mature virions from the host cell occurs through either lytic or non-lytic mechanisms.

Figure 2

Schematics of the EV-A71 genome, translation, and polyprotein processing. (A) The EV-A71 genome and secondary structure loops (SLs) are depicted as a black line and circles, respectively. The 5′-UTR of EV-A71 encompasses SLs I–VI (black line), with SLs II–VI constituting the type I IRES. The viral major open reading frame (mORF) encodes a polyprotein precursor, which is proteolytically processed into four structural proteins (indicated with blue blocks) and seven non-structural proteins (2A–2C indicated with green, 3A–3D in yellow, respectively). Additionally, a small upstream open reading frame (uORF) is indicated by a purple block, initiated from the first in-frame AUG codon (AUG1). The 3′-UTR of EV-A71 contains domains designated as -X, -Y, and -Z, which are implicated in genome RNA replication. (B) A schematic illustration of the translation and processing of the EV-A71 polyprotein is presented, highlighting the primary roles of 2A^pro and 3C^pro proteases in these processes. (C) Four types of classical viral IRES. IRESs are generally categorized into four types based on their essential eIFs and ITAFs, secondary structure, and other biological properties. Some well-known ITAFs binding to the domain are shown. Notable domains within the IRES are color-coded: C-rich regions are in brown, representing areas with a high cytosine content; GNRA motifs are in blue, where G is for guanine, N for undefined nucleotides, R for purine (adenine or guanine), and A for adenine; Yn regions are in green, indicating pyrimidine-rich sequences approximately 8 to 10 nucleotides in length. Thin line junctions denote known pseudoknot structures within the IRES (adapted from references [21,68]).

Figure 3

Schematics of EV-A71 genome replicative-relative complexes, including RNPs and ROs. (A) EV-A71 replicative RNPs. Interactions between viral proteins (3CD, 3AB, 3D^pol, and VPg) and host cell proteins (PCBP and PABP) with specific cis-regulatory elements of EV-A71 are depicted. These interactions mainly occur at stem-loop I (SL I), which includes four subdomains as alphabetically indicated with a-d, the cis-acting replication element (CRE), and the 3′-poly(A) tract. (B) EV-A71 replicative organelles and lipid droplets. Proteins 2C and 2BC facilitate the tethering of lipid droplets (LDs) and replication complexes (RCs). Additionally, 3A and 2BC proteins interact with host lipases ATGL and HSL, promoting the recruitment of lipolytic machinery to the LD-RC interface. These replication complexes are anchored to mature ROs.