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.