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. Author manuscript; available in PMC: 2021 Sep 29.
Published in final edited form as: Annu Rev Virol. 2020 Jun 30;7(1):421–446. doi: 10.1146/annurev-virology-011720-095930

Table 1.

Human viruses reported to be sensitive to the antiviral effects of viperin

Family Virus Experimental evidence Proposed domain(s) requireda Proposed mechanism(s) of action Reference(s)
Herpesviridae (dsDNA group) HCMV Overexpression of viperin, knockdown of viperin, co-IPs, microscopy RS domain Antiviral effects only if expressed prior to infection through an unknown mechanism; proviral: the HCMV vMIA protein binds to viperin and localizes it to the mitochondria where it binds to host proteins, altering cellular metabolism that favors HCMV replication; replacing the N terminus for a mitochondrial targeting signal is sufficient 3, 22, 23
KSHV Overexpression of viperin, knockdown of viperin, co-IP, pharmacological disruption of lipid droplets, in vitro oxidation assays Controversial—authors proposed protein methionines are substrates for viperin despite published biochemical evidence to the contrary Proviral: binds to and promotes methionine oxidation of the KSHV helicase ORF44, which in turn enhances its stability 69
Flaviviridae (+ssRNA group) Hepatitis C virus Overexpression of viperin, knockdown of viperin, replicons, FRET analysis, in vitro primer extension assays with purified RdRp RS and aromatic amino acids on C terminus required when using replicon colony formation assays; C terminus required for binding to VAP-A and NS5A; role for the N terminus is controversial Binds to NS5A through its C terminus and to the host factor VAP-A in replication complexes, which may interfere with viral replication; chain termination of RNA replication through ddhCTP-dependent inhibition of RdRp 1, 20, 75, 78
West Nile virus Overexpression of viperin, replicons, Viperin−/− mice, in vitro primer extension assays with purified RdRp RS domain and N terminus (only partially) Inhibition is seen in virus-like particles and subgenomic replicons; likely chain termination of RNA replication through ddhCTP-dependent inhibition of RdRp 1, 76, 94
Dengue virus type 2 Overexpression of viperin, knockdown of viperin, replicons, FRET analysis, in vitro primer extension assays with purified RdRp Controversial—RS domain required when using VLP; only C terminus required during infection Inhibition is seen in VLPs, subgenomic replicons, and infections; interacts with capsid and NS3; likely chain termination of RNA replication through ddhCTP-dependent inhibition of RdRp 1, 19, 76
Zika virus Overexpression of viperin, viperin knockout cells, microscopy, co-IPs, in vitro primer extension assays with purified RdRp, addition of exogenous ddhCTP to cells C-terminal domain (especially the last four amino acids); N-terminal and RS domains are indispensable Likely interferes with RNA replication; interacts with NS3 and promotes its degradation; chain termination of RNA replication through ddhCTP-dependent inhibition of RdRp 1, 28, 77, 79, 95
Tick-borne encephalitis virus Overexpression of viperin, depletion of CIAO1, Fe55 incorporation, SAM depletion, flotation assays, microscopy, co-IPs RS domain and incorporation of Fe are required; aromatic residues in C terminus are required for maturation of viperin and Fe incorporation Inhibits viral +ssRNA synthesis through an RS-dependent mechanism; interacts with structural and nonstructural proteins and promotes degradation of NS3; induces release of noninfectious capsids and may prevent virion maturation by promoting Golgi-independent secretion of capsids 29, 77, 82
JEV Overexpression of viperin in presence of proteasome inhibitor ND Viperin is normally degraded in JEV-infected cells; inhibition of the proteasome rescues the antiviral properties of viperin by an unknown mechanism 56
Langat virus Flotation assays, microscopy, Viperin−/− mice ND Unknown; proposed to be through induction of secretion of noninfectious capsids; cell-type-specific effects in vivo 82, 96
Picornaviridae (+ssRNA group) Human rhinovirus Viperin knockdown ND Unknown; unlikely to be dependent on ddhCTP production 1, 97
Enterovirus A71 Overexpression of viperin, knockdown of viperin, co-IP N-terminal domain Binding to viral protein 2C at the ER through its N-terminal domain 98
Togaviridae (−ssRNA group) Chikungunya virus Overexpression of viperin, Viperin−/− mice, colocalization with nsP2 at the ER N-terminal domain is sufficient; intact RS domain is required in full-length viperin Unknown 81
Sindbis virus Viperin knockdown ND Unknown 56, 99
Rhabdoviridae (−ssRNA group) Rabies virus Overexpression of viperin RS domain Reduction of cholesterol and sphingomyelin at the plasma membrane; likely inhibition of virion budding through alteration of lipid rafts 86
Vesicular stomatitis virus Knockdown of viperin ND Unknown; proposed to be due to viperin-mediated promotion of RIG-I oxidation and stabilization 69
Orthomyxoviridae (−ssRNA group) Influenza A virus Overexpression of murine viperin in human cells; however, no effect observed in Viperin−/− mice ND Disruption of lipid rafts inhibits virus release from the plasma membrane 70, 100
Arenaviridae (−ssRNA group) Junín mammarenavirus Overexpression of viperin and coimmunoprecipitations N-terminal domain Binds to viral N protein through its N-terminal domain at LDs and inhibits mRNA synthesis 101
Peribunyaviridae (−ssRNA group) Bunyamwera orthobunyavirus Overexpression of viperin RS domain (only domain tested) Unknown 102
Paramyxoviridae (−ssRNA group) Respiratory syncytial virus Overexpression of viperin in cell culture and in chinchillas, microscopy ND Unknown; may interfere with virus filament formation and cell-to-cell spread 103, 104
Measles virus Overexpression of viperin N terminus, RS domain, C terminus Inhibits virus release; no effects on titers of cell-associated virus 85
Retroviridae (ssRNA-RT group) Human immunodeficiency virus-1 Knockdown of viperin, overexpression of viperin, microscopy RS domain; N-terminal and C-terminal domains are indispensable Disruption of lipid rafts and inhibition of virion release from the plasma membrane; intact RS domain is required for redistribution of viperin to sites of virion release 84

Abbreviations: CIA, cytosolic iron-sulfur protein assembly; co-IP, coimmunoprecipitation; ddhCTP, 3′-deoxy-3′, 4′-didehydro-cytidine triphosphate; dsDNA, double-stranded DNA; ER, endoplasmic reticulum; FRET, fluorescence resonance energy transfer; HCMV, human cytomegalovirus; JEV, Japanese encephalitis virus; KSHV, Kaposi’s sarcoma-associated herpesvirus; LD, lipid droplet; mRNA, messenger RNA; ND, not determined; NS3, nonstructural protein 3; NS5A, nonstructural protein 5A; nsP2, nonstructural protein 2; RdRp, RNA-dependent RNA polymerase; RIG-I, retinoic acid-inducible gene I; RS, radical S-adenosyl-L-methionine; RT, reverse transcriptase; SAM, S-adenosyl-L-methionine; ssRNA, single-stranded RNA; VAP-A, vesicle-associated membrane protein-associated protein-A; VLP, virus-like particle; vMIA, viral mitochondrial inhibitor of apoptosis.

a

Biochemical evidence indicates that neither the RS nor the C-terminal domain can operate independently, and their functions cannot be separated.