The NiV particle has six structural proteins, namely the N, P, M, F, G and L, which are arranged accordingly in the RNA genome from 3′ to 5′ (Figure 1) [6]. The replication cycle of NiV starts when the virion attaches to the host cell receptors, ephrin-B2 and -B3 via the NiV G protein [31,32,33]. Next, the NiV F protein mediates the fusion of the viral envelope with the host cell membrane, releasing the viral genome into the cytoplasm. The viral genomic RNA is associated with N, P and L proteins, which forms the ribonucleoprotein complex and is involved in the transcription and replication of the virus. The L polymerase catalyzes the transcription of the virus genomic RNA into mRNAs for protein translation. The translated viral surface glycoproteins F and G are inserted into the host cell endoplasmic reticulum for post-translational modifications, particularly glycosylation. The other translated viral proteins—N, P, M and L—remain in the cytoplasm. When abundant viral mRNA transcripts are produced, full-length anti-genomes are then synthesized to generate more copies of the NiV genome. These new copies of genome assemble with the viral proteins near the host cell membrane where F and G proteins are studded, and the budding of new virions facilitated by the M protein will occur.

NiV enters through the oronasal route into human and other animal hosts to cause an infection. The virus infects the epithelium cells along the respiratory tract, and a high concentration of viral antigens could be detected in the lymphoid and respiratory tissues [12]. Initial viremia then spreads the virus to other parts of the body, while secondary replication occurs in the endothelium. The NiV infection of host cells starts when the viral G protein attaches to the cellular receptors ephrin-B2 and -B3 [31,32,33]. The virus then rapidly disseminates to different organs, including the spleen, kidneys, heart and liver within the first week of infection [14,34,35]. Both ephrin-B2 and -B3 are found on a wide range of cell types including epithelial and endothelial cells, as well as neurons. Both these cellular receptors are highly conserved across animal species, which explains the broad species and tissue tropism of NiV [36]. Interestingly, a recent study has observed that smooth muscle cells that lack the cellular receptors ephrin-B2 and -B3 were permissive to NiV infection and produced high viral titers similar to permissive cells expressing the cellular receptors [37]. There was prolonged NiV production in the smooth muscle cells with no cytopathogenic effects. Together, the study suggested the likely existence of an unidentified entry receptor for NiV or a non-specific virus entry mechanism. Besides, NiV was also reported to enter and infect the central nervous system via circulating immune cells, specifically immature dendritic cells and monocytic cells [38]. These cells were noted to be NiV-permissive; however, the virus did not replicate efficiently in them. Nevertheless, the NiV-infected immune cells migrated across the in vitro blood–brain barrier and infected susceptible cells in a focused manner, similar to observed neuronal infection and the presence of focal lesions in the brain of both NiV-infected human and animals [39,40].