TABLE 1.

Examples for endogenous retroviruses involved in immunity

Mode of action	ERVb	Species (examples)	Molecular mechanisma	Target virus(es)	Reference(s)
Induction of sensing via nucleic acids	Multiple ERVs (e.g., ERV3-2, ERV4700)	Humans	Sensing of ERV-derived nucleic acids by MDA5, RIG-I, and TLR3	Most likely several viruses	15, 20–23
	ALVE1	Chickens	Induction of TLR3 signaling by ERV-derived lncRNA (lnc-ALVE1-AS1)	Avian leukosis virus subgroup J, possibly others	18
Regulation of immune signaling by lncRNAs	lnc-EPAV	Mice	lncRNA-mediated sequestration of SFPQ, a repressor of Rela expression	VSV, possibly others	25
	MER9a2, LTR5A, MLT2A1	Humans	Binding of SFPQ; induction of Rela expression (?)	Most likely several viruses	25
Modulation of immune activation by ERV proteins	HERV-W Env	Humans	Activation of TLR4/CD14; induction of IL-1β, IL-6, TNF-α, and IL-12p40	Most likely several viruses	26
	HERV-K(HML2) dUTPase	Humans	Activation of NF-κB via TLR2; induction of IL-1β, IL-6, IL-8, IL-10, IL-12p40, IL-23, IL-17, TNF-α, RANTES, IFN-γ, and CCL20	Most likely several viruses	28
Receptor interference	ev3, ev6, ev9	Chickens	Receptor blockade	Avian leukosis virus, subgroup E	40
	Fv-4r (Akvr-1)	Mice	Blockade of the receptor CAT-1	Ecotropic murine leukemia viruses	41, 42, 46
	Rcmf, Rcmf2	Mice	Blockade of the receptor XPR1	Polytropic murine leukemia viruses	47–51
	en-JSRV env loci	Sheep	Blockade of the receptor hyaluronidase 2 (HYAL2)	Jaagsiekte sheep retrovirus, enzootic nasal tumor virus (?)	52
	Refrex-1 (loci ERV-DC7 and –DC16)	Cats	Secreted truncated Env; extracellular receptor interference	Endogenous and exogenous feline retroviruses (ERV-DC genotype I, FeLV-D)	54
	FeLIX	Cats	Secreted truncated Env; extracellular receptor interference	FeLV-B	55
	HERV-T env locus	Primates	Depletion of MCT-1 from the cell surface	Extinct HERV-T ancestor	56
	Suppressyn	Primates	Blockade of the receptor ASCT2	RD114/mammalian type-D retroviruses	57
Dominant negative virion complementation	Fv-4r	Mice	Virion incorporation of Env with inactive fusion peptide	Ecotropic murine leukemia viruses	58
	HERV-K gag locus	Humans	Coassembly with exogenous viral Gag; generation of malformed and poorly infectious virions; reduced virion release	HIV-1	62, 63
	enJS56A1, enJSRV-20 (?)	Sheep	Dominant negative interference of a defective Gag protein with viral exit	Jaagsiekte sheep retrovirus	64–66
Interference with incoming viral particles	Fv1	Mice	Binding to incoming capsids	Murine leukemia viruses	67–70
Increased plasticity of immune genes	Multiple ERVs	Several species	Gene conversion and duplication events increasing the diversity of MHC II genes and potentially others	Most likely several viruses	85
Regulation of antiviral gene expression	X-MLV LTR	Mice	Enhancer of mA3; increase in the levels and antiviral activity of APOBEC3	MMTV, potentially others	91, 92
	HERVP71A LTR/enhancer L	Humans	Enhancer of HLA-G	Unclear	93, 94
	MER41	Humans	IFN-γ-inducible enhancer of AIM2 expression	Most likely several viruses	97
	MER41	Humans	IFN-γ-inducible enhancer of IFI6 expression	Several flaviviruses	97
	MER41	Humans	IFN-γ-inducible enhancer of SECTM1 expression	Most likely several viruses	97
	ERV9	Apes	Transcription start site for IRGM	Active against mycobacteria, antiviral activity unclear	105
	LTR12C	Humans	IFN-γ-inducible promoter of GBP2	HIV, measles virus, Zika virus, and other furin-dependent viral pathogens	107
	LTR12C	Humans	Promoter of GBP5	HIV, measles virus, Zika virus, and other furin-dependent viral pathogens	107
	LTR12C	Humans	Promoter of SEMA4D (?)	Multiple viruses?	107

^aTLR, Toll-like receptor; IL, interleukin; TNF-α, tumor necrosis factor alpha; IFN-γ, gamma interferon; lncRNA, long noncoding RNA.

^bLTR, long terminal repeat.