Figure 4. Schematic overview of the replication of some hantaviruses.
The attachment and entry of hantaviruses into host cells are mediated by the binding of viral glycoproteins to host cell surface receptors.61 Some hantaviruses attach and enter host cells through integrins (e.g., αVβ3 and αVβ1), which are transmembrane heterodimer glycoproteins composed of α and β subunits.60 In addition to integrins, decay acceleration factors (e.g., DAF/CD55) and complement receptors (e.g., gC1qR/P32) have also been proposed as candidate cell attachment factors for some hantaviruses.60 Protocadherin-1 likely played a role in the attachment and entry of all NWHVs in the last two years.62 After attachment to cell surface receptors, hantaviruses rely on several pathways for entry, including macropinocytosis and endocytosis, which are either clathrin-, calveolin-, or cholesterol-dependent.60 For instance, HTNV and SEOV are internalized by clathrin-mediated endocytosis. ANDV can be internalized through cholesterol-mediated micropinocytosis.60
After internalization, virions form clathrin-coated vesicles, which can be formed with clathrin-coated cell membranes.61Virions are then transported to the early endosomes, and eventually to the late endosomes and lysosomal compartments. The membrane fusion of the viral envelope with the endosome is accompanied by a decrease in pH value, from the weak acidity of the early endosome to the strong acidity of the late endosome. Hantavirus requires acidity (pH 5.8−6.3) for membrane fusion.63 Gc is a type II viral fusion protein. The conformational change of Gc is triggered by endosomal acidification, and then the Gc fusion peptide is inserted into the endosomal membrane, leading to further conformational change, which mediates the fusion of the viral envelope and endosomal membrane.64
The fusion of the viral envelope and endosomal membrane promotes the release of the viral ribonucleoproteins (RNP) complex into the cytoplasm, initiating the transcription and replication of the viral genome.31 RdRp mediates the transcription and replication of the viral genome, and the replication of the hantavirus genome only occurs in the cytoplasm.7 Both the 5’- and 3’- ends of vRNA have non-coding regions (NCR), which are complementary sequences. vRNA replicates into complementary RNA (cRNA), which serves as a template for vRNA replication. Genome replication starts from scratch and proceeds through forward cRNA, which replicates out vRNA and is encapsulated by nucleocapsid (N) proteins to form RNPs.61
N proteins play a variety of roles in the viral replication cycle. They participate in transcription together with viral RdRp to promote mRNA translation.31 RdRp initiates transcription through a unique cap-snatching mechanism that produces the viral mRNAs. The N-terminal of the L protein has endonuclease activity, which can cut capped primers from mRNA of host cells and be used to synthesize viral mRNAs (cap-snapping).31 The viral mRNAs transcribed from the L and S segments of the genome are translated on episomal ribosomes, and the viral mRNAs transcribed from the M segments in membrane-bound ribosomes are translated in the endoplasmic reticulum (ER) and rough endoplasmic reticulum (RER).65
The viral GPC is cleaved in the ER into the Gn and Gc glycoproteins at the conserved pentapeptide motif WAASA,31 which are further glycosylated in the ER and transported to the Golgi complex, where they form heterodimers.66 Gn and Gc are modified by N-glycan chains, which stabilize the spike structure and play a key role in the virion assembly.64 All virions are assembled in the Golgi apparatus, and the newly synthesized virions bud into the Golgi pool, during which the cytoplasmic tail of Gn interacts with the RNP complex.60 The virions are then transported to the cell membrane, where they are released by exocytosis. Hantaviruses are usually assembled at the Golgi apparatus, and some hantaviruses could be assembled at the plasma membrane by fusion of viral vesicles and cell membranes.31
The host mechanisms of innate and acquired immunity in mammals are crucial to inhibiting hantavirus replication.67Despite various advances in this field in recent years, many key aspects of hantaviruses replication cycle remain unknown, particularly regarding the mechanisms involved in genome replication, transcription, translation, and viral assembly.