Table 1.

Viral and Host Factors That Regulate the Formation of DIPs

Virus	Genomic or protein level	Host or viral factor	De novo generation, replication, or packaging	Proposed mechanism ofaction	Refs
Lymphocytic choriomeningitis virus	Protein	Viral: Z matrix protein	Unknown	The PPXY late domain in the viral Z protein promotes DIP production	[28]
Lymphocytic choriomeningitis virus	Not applicable (n/a)	Host: ESCRT, host kinases, Nedd4 family E3 ubiquitin ligases	Unknown	Thecellular ESCRT pathway, host kinase-driven phosphorylation of the viral matrix protein, and certain Nedd4 family E3 ubiquitin ligases promote DIP production	[28,78,79]
Respiratory syncytial virus	Genomic	Viral	De novo	Nucleotide composition at specific sites in the genomic RNA increases the rate at which the viral polymerase generates copy-back DVGs	[59]
Influenza A virus	Unkown	Viral	Unknown	A mutation in the PA subunit in the polymerase results in a significant increase in DIPs. Function could be at the genomic level as the mutation in PA results in increased levels of DVGs with mutations in genome segment containing PA. The mutation could also affect the ability of PA to stay bound to the RNA template which would increase the chances of aberrant RNA replication	[74]
Influenza A virus	Protein	Viral	De novo	Mutations in NS2 increase generation of DIPs specifically containing deletions in PA gene	[69]
Vesicular stomatitis virus	n/a	Host	De novo	Human chromosome 16 in human–mouse somatic cell hybrids suppressed de novo generation of DVGs	[75]
Rabies virus	Genomic	Virus	Replication	Promoter strength of an engineered copy-back DVG permitted strongly biased amplification of the DVG over full-length genomes	[65]
Influenza A virus	Genomic	Viral	n/a packaging	IAV DVGs are packaged into virus particles more efficiently than their cognate full-length genomes	[24,66,67]
Influenza A virus	Genomic	Viral	Replication	A specific type of IAV DVGs has a mutation in its replication promoter that substantially increases the rate of replication relative to wild-type genomes	[61]
Vesicular stomatitis virus, Sendai virus	Genomic	Viral	Replication	Complementary ends and a lack of a transcriptional promoter allow 5′ copy-back and snap-back DVGs to replicate at a higher rate than full-length genomes	[61–64]
Influenza A virus	Likely Protein	Viral	Unknown	A mutation (D529N) in the PA subunit of the polymerase inhibited the production of DVGs	[41]
Influenza A virus	Likely Protein	Viral	Unknown	Mutations in M1 and M2 increase the production of DVGs	[41,73]
Sendai virus, measles virus	Likely protein	Viral	Unknown	The C protein suppresses DVG production	[36,70,71]
Sendai virus	Protein	Viral	De novo	A point mutation in the N protein increases production of DVGs, possibly by the lower density of viral nucleocapsids	[68]
Influenza A virus	Protein	Viral	Unknown	The NS gene segment from a highly pathogenic H5N1 IAV induces robust production of DIPs compared with the NS gene segment from H1N1	[70]