Table 1.

Helper virus factors involved in supporting adeno-associated virus (AAV) replication.

Helper Virus	Gene Product	Native Function	Helper Function	Essential For AAV	References
HSV-1	UL5	HP complex helicase subunit, unwinds DNA at replication fork	Promotes AAV genome replication, requires UL5 helicase activity	Yes	[132,135]
	UL8	HP complex subunit, stimulates enzymatic activity of UL5 and UL52	Promotes AAV genome replication	Yes	[132,135]
	UL52	HP complex primase subunit, primase activity during DNA replication	Promotes AAV genome replication	Yes	[132,135]
	ICP8	ssDNA binding protein, required for HSV-1 genome replication	Promotes AAV genome replication, binds Rep78 and AAV ssDNA	Yes	[132,133]
	ICP0	E3 ubiquitin ligase, trans-activator of HSV-1 gene expression	Supports AAV Rep-expression	No	[139]
	ICP4	Major viral transcription factor	Supports AAV Rep-expression	No	[139]
	ICP22	Transcriptional regulator	Supports AAV Rep-expression	No	[139]
	UL30	HSV-1 polymerase catalytic subunit	Enhances AAV genome replication	No	[139,148]
	UL42	HSV-1 polymerase subunit	Enhances AAV genome replication	No	[139,148]
AdV5	E1A	General transcription factor, AdV early promoter activation, oncogene	AAV promoter activation, drives cells to S-phase	Yes	[190,192,194,195,211]
	E1B19K	Inhibits proapoptotic Bcl-2 homologs (Bax and Bak), induces autophagy, oncogene	Enhances AAV vector titers	No	[211,212]
	E1B55K	In complex with E4orf6 it prevents E1A mediated p53 stabilization, oncogene	Involved in AAV mRNA export, promotes AAV second-strand synthesis	Yes	[153,175,197,199,211,212]
	protein IX	Minor component of the AdV capsid, capsid stability	Molecular function unclear, enhances AAV vector titers	No	[211]
	E2A	ssDNA binding protein, viral DNA replication & mRNA processing	AAV promoter regulation, AAV genome replication, Rep splicing, capsid protein production	Yes	[193,200,201,202,203,204,211]
	E4orf6	In complex with E1B55K it prevents E1A mediated p53 stabilization, supports viral DNA replication and RNA processing	Promotes AAV second-strand synthesis, inhibits the MRN complex	Yes	[29,153,193,198,201,205,208]
	VA RNA	inhibits the eIF-2 protein kinase, promotes viral protein translation	Prevents E4orf6/E1B mediated degradation of AAV capsids & Rep52	Yes	[29,189,193,201,210]
HPV-16	E1	HPV-16 DNA replication, binds origin of DNA replication on the HPV-16 genome	Binds AAV Rep-ITR, nicking activity, complements AdV5 helper factors, increases rAAV titers, augments rep and cap expression	No	[220,221,222,224,225]
	E2	Increases p53 levels, activates transcription, inhibits E6	Enhances AAV titers	No	[10,222]
	E6	Oncogene	Complements AdV5 helper factors, increases rAAV titers, augments rep and cap expression	No	[219,220,222]
HBoV1	NS2	Trans-activation of viral promoters	Promotes AAV second-strand synthesis, not essential when AAV genome is a duplex	(Yes)	[12,226]
	NS4	Trans-activation of viral promoters	Activation of AAV promoter	(Yes/No) 1	[12,226]
	NP1	Processing of viral pre-mRNA, trans-activation of viral promoters	Activation of AAV promoter	Yes	[12,226]
	BocaSR	Regulates NS1, NS2, NS3, NP1 expression and viral DNA replication	Not known	Yes	[12,226]

Essentiality is unclear ¹.