Ca²⁺ is essential for virus entry, viral gene replication, virion maturation, and release. The alteration of host cells Ca²⁺ homeostasis is one of the strategies that viruses use to modulate host cells signal transduction mechanisms in their favor. Host calcium-permeable channels and pumps (including voltage-gated calcium channels, store-operated channels, receptor-operated channels, transient receptor potential ion channels, and Ca²⁺-ATPase) mediate Ca²⁺ across the plasma membrane or subcellular organelles, modulating intracellular free Ca²⁺. Therefore, these Ca²⁺ channels or pumps present important aspects of viral pathogenesis and virus–host interaction. It has been reported that viruses hijack host calcium channels or pumps, disturbing the cellular homeostatic balance of Ca²⁺. Such a disturbance benefits virus lifecycles while inducing host cells’ morbidity. Evidence has emerged that pharmacologically targeting the calcium channel or calcium release from the endoplasmic reticulum (ER) can obstruct virus lifecycles. Impeding virus-induced abnormal intracellular Ca²⁺ homeostasis is becoming a useful strategy in the development of potent antiviral drugs. In this present review, the recent identified cellular calcium channels and pumps as targets for virus attack are emphasized.

Enterovirus 71 (EV71) is an etiologic agent of hand-foot-and-mouth disease (HFMD), and recent HFMD epidemics worldwide have been associated with a severe form of brainstem encephalitis associated with pulmonary edema and high case-fatality rates. EV71 contains a positive-sense single-stranded genome RNA of approximately 7400 bp in length which encodes a polyprotein with a single open reading frame (ORF), which is flanked by untranslated regions at both the 5' and 3' ends.

The recent outbreak of novel coronavirus pneumonia (COVID-19) caused by a new coronavirus has posed a great threat to public health. Identifying safe and effective antivirals is of urgent demand to cure the huge number of patients. Virus-encoded proteases are considered potential drug targets. The human immunodeficiency virus protease inhibitors (lopinavir/ritonavir) has been recommended in the global Solidarity Trial in March launched by World Health Organization. However, there is currently no experimental evidence to support or against its clinical use. We evaluated the antiviral efficacy of lopinavir/ritonavir along with other two viral protease inhibitors in vitro, and discussed the possible inhibitory mechanism in silico. The in vitro to in vivo extrapolation was carried out to assess whether lopinavir/ritonavir could be effective in clinical. Among the four tested compounds, lopinavir showed the best inhibitory effect against the novel coronavirus infection. However, further in vitro to in vivo extrapolation of pharmacokinetics suggested that lopinavir/ritonavir could not reach effective concentration under standard dosing regimen [marketed as Kaletra^®, contained lopinavir/ritonavir (200 mg/50 mg) tablets, recommended dosage is 400 mg/10 mg (2 tablets) twice daily]. This research concluded that lopinavir/ritonavir should be stopped for clinical use due to the huge gap between in vitro IC₅₀ and free plasma concentration. Nevertheless, the structure–activity relationship analysis of the four inhibitors provided further information for de novel design of future viral protease inhibitors of SARS-CoV-2.

Human Enterovirus 71 (EV71) has emerged as the leading cause of viral encephalitis in children, especially in the Asia-Pacific regions. EV71 vaccine development is of high priority at present, and neutralization antibodies have been documented to play critical roles during in vitro and in vivo protection against EV71 infection.

RNA editing is an important mechanism that expands the diversity and complexity of genetic codes. The conversions of adenosine (A) to inosine (I) and cytosine (C) to uridine (U) are two prominent types of RNA editing in animals. The roles of RNA editing events have been implicated in important biological pathways. Cellular RNA editing activity in response to influenza A virus infection has not been fully characterized in human and avian hosts. This study was designed as a big data analysis to investigate the role and response of RNA editing in epithelial cells during the course of infection with various subtypes of influenza A viruses. Using a bioinformatics pipeline modified from our previous study, we characterized the profiles of A-to-I and C-to-U RNA editing events in human epithelial cells during the course of influenza A virus infection. Our results revealed a striking diversity of A-to-I RNA editing activities in human epithelial cells in responses to different subtypes of influenza A viruses. The infection of H1N1 and H3N2 significantly up-regulated normalized A-to-I RNA editing levels in human epithelial cells, whereas that of H5N1 did not change it and H7N9 infection significantly down-regulated normalized A-to-I editing level in A549 cells. Next, the expression levels of ADAR and APOBEC enzymes responsible for A-to-I and C-to-U RNA editing during the course of virus infection were examined. The increase of A-to-I RNA editing activities in infections with some influenza A viruses (H1N1 and H3N2) is linked to the up-regulation of ADAR1 but not ADAR2. Further, the pattern recognition receptors of human epithelial cells infected with H1N1, H3N2, H5N1 and H7N9 were examined. Variable responsive changes in gene expression were observed with RIG-I like receptors and Toll like receptors. Finally, the effect of influenza A virus infection on cellular RNA editing activity was also analyzed in avian hosts. This work represents the first comprehensive study of cellular RNA editing activity in response to different influenza A virus infections in human and avian hosts, highlighting the critical role of RNA editing in innate immune response and the pathogenicity of different subtypes of influenza A viruses.