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.

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