Abstract
Alphavirus non-structural proteins 1–4 (nsP1, nsP2, nsP3, and nsP4) are known to be crucial for alphavirus RNA replication and translation. To date, nsP3 has been demonstrated to mediate many virus–host protein–protein interactions in several fundamental alphavirus mechanisms, particularly during the early stages of replication. However, the molecular pathways and proteins networks underlying these mechanisms remain poorly described. This is due to the low genetic sequence homology of the nsP3 protein among the alphavirus species, especially at its 3′ C-terminal domain, the hypervariable domain (HVD). Moreover, the nsP3 HVD is almost or completely intrinsically disordered and has a poor ability to form secondary structures. Evolution in the nsP3 HVD region allows the alphavirus to adapt to vertebrate and insect hosts. This review focuses on the putative roles and functions of indel, repetition, and duplication events that have occurred in the alphavirus nsP3 HVD, including characterization of the differences and their implications for specificity in the context of virus–host interactions in fundamental alphavirus mechanisms, which have thus directly facilitated the evolution, adaptation, viability, and re-emergence of these viruses.
Highlights
The Alphavirus genus belongs to the Togaviridae family, together with Rubivirus and unclassified Togaviridae genera
Based on the aforementioned findings and the ability of CHIKVs and other alphaviruses to use a few different strategies for survival in host cells, such as having an opal stop codon in nsP3 to create a more persistent CHIKV infection in the host [125], we suggest that the existence of duplication events in both AURAV and CHIKV nsP3 hypervariable domain (HVD) are an indication of the virus adaptation to their interactions with host cellular proteins to give them a suitable replication rate for survival and transmission during their co-existence with DENVs
The nsP3 HVD has been recorded to bind to several distinctive individual host cellular proteins and has been demonstrated to be involved in alphavirus replication, vector specificity, and virulence determination
Summary
The Alphavirus genus belongs to the Togaviridae family, together with Rubivirus and unclassified Togaviridae genera. The alphavirus nsP3 has been demonstrated to be involved in replication and viral transmission, either inter-host or among different hosts It plays a role as a determinant of alphavirus virulency and vector specificity, and regulates host stress responses during viral infection. These roles and functions are based on specific virus–host modes of interactions, i.e., between specific individual alphavirus nsP3 HVDs and specific sets of host cellular proteins [13]. The present review compiles and summarizes recent genetic research on alphavirus nsP3, its HVD, and discusses potential mechanisms linked to its genetic information It focuses on the roles and effects of indel, repetitive, and duplication events occurring in the alphavirus nsP3 HVD in determining the specificity of virus–host interactions in fundamental viral mechanisms. These ubiquitous mutation events have contributed to alphavirus evolution, viability, and re-emergence
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