Defective viral genomes are key drivers of the virus-host interaction

Abstract

Viruses survive often harsh host environments, yet we know little about the strategies they utilize to adapt and subsist given their limited genomic resources. We are beginning to appreciate the surprising versatility of viral genomes and how replication-competent and -defective virus variants can provide means for adaptation, immune escape and virus perpetuation. This Review summarizes current knowledge of the types of defective viral genomes generated during the replication of RNA viruses and the functions that they carry out. We highlight the universality and diversity of defective viral genomes during infections and discuss their predicted role in maintaining a fit virus population, their impact on human and animal health, and their potential to be harnessed as antiviral tools.

Fig. 1. Classes of DVGs.

a, Mutations in the viral genomes can lead to the generation of DVGs. These mutations can be single point mutations, hypermutations or frameshift mutations that alter virus replication, viral protein expression and/or viral protein function. b, Deletion-type DVGs occur when the polymerase skips part of the genome during replication and generates a truncated version of the genome. Deletion DVGs could also involve genomic rearrangements and gene duplication. Deletion generally results in lost or altered expression of one or more genes. c, Snap-back and copy-back DVGs are generated in nsRNA viruses when a sequence is duplicated in reverse complement to create theoretical panhandle structures for copy-back DVGs or hairpin structures for snap-back DVGs. Complementary sequence duplication occurs when the polymerase is released from the template strand and reattaches back to the nascent strand, copying back the end of the nascent genome. They can also occur from the polymerase copying back another complementary genome bound in trans. Most described snap-back and copy-back DVGs are generated from the 5’ end of the genome with the complementary end containing a duplication of the unstranslated region (UTR). Various degrees of complementation within Gene Z in the illustrated model can be found in copy-back DVGs. These types of genomes are not transcribed but can be replicated by the viral polymerase.

Fig. 2. Mechanisms of DVG generation.

a, Variations in the viral RdRp fidelity due to mutations or effects of virus-encoded co-factors, such as the influenza A virus (IAV) NEP or the paramyxovirus C protein, can favour the generation of DVGs. b, Variants of the nucleoprotein with altered binding to viral RNA can promote DVG generation. c, Variants of structural proteins, such as the PPXY domain in the matrix protein of arenaviruses, can lead to DVG generation. d, Inter- and intra-recombination events using homologous sequences (red) can lead to the formation of deletion DVGs.

Fig. 3. Functions and modes of actions of DVGs.

a, Overview of the known effects of DVGs on the standard virus and host cells, as well as their impact on viral pathogenesis. b, Proposed mechanism of competition for viral products in cells containing several copies of standard virus and DVGs, resulting in ‘interference’. (1) The viral polymerase replicates DVGs more efficiently than standard virus due to their shorter length and flanking trailer promoters. (2) These DVG properties lead to faster accumulation of DVGs in the infected cell. (3) DVGs eventually outcompete standard virus to become the predominant species and interfere with standard virus replication. c, Proposed mechanism for immunostimulation and cell survival induced by copy-back DVGs. Infected cells first detect DVGs through the RNA sensors RIG-I or MDA5, which signal through the adaptor protein MAVS for the production and secretion of type I and III IFNs pro-inflammatory cytokines and pro-survival proteins.