Viruses can be differentiated based on how they store their genomic information, such as by DNA or double-stranded RNA. Positive-sense single-stranded RNA (+ssRNA) viruses are one such way and it is a key aspect of the infectious cycle of the virus. Two important examples of +ssRNA viruses are SARS-CoV-2 and Hepatovirus A, which cause coronavirus and hepatitis A, respectively.
Replication of +ssRNA viruses
Replication of +ssRNA genomes occurs in the cytoplasm of the host cell and often occurs in tandem with the assembly of the nucleocapsid into which the genetic material is packaged. However, there are some exceptions to this, such as Enterovirus. This differs from the replication of double-stranded DNA and RNA viruses, where empty capsids are made first and later filled by the genome.
The close relationship between replication of the viral genome and nucleocapsid formation means that genomic RNA and the capsid protein are highly specific for each other. Despite this, +ssRNA viruses are a diverse category of viruses, and RNA replication and packaging specificity can differ between closely related viruses.
In many cases, the replication of +ssRNA viruses occurs spontaneously, without ATP and thus no energetic cost. In vitro experiments have also shown that +ssRNA viral assembly depends on interactions between proteins and between proteins and RNA. The genomes are the templates for translation and replication, which is what fosters interactions between the host’s replication factors and RNA replication at several levels.
Importance of +ssRNA viruses
Positive-sense RNA viruses make up more than one-third of all known virus genera. This includes important pathogens, but also many viruses on official lists of potential bioterrorism agents. These types of viruses use host factors in all steps of viral infection, such as entry and replication. Perhaps more importantly, +ssRNA viruses can modulate the gene expression and defenses of the host by co-opting host factors.
The genome RNA of a +ssRNA virus contains only the genes needed for the infectious cycle and is simultaneously a messenger RNA. Its packaging depends on several different segments, which is believed to be an adaptation to withstand mutations. Given the close relationship between the RNA and proteins, a mutation could interrupt the infectious cycle if the packaging relied on a limited number of genes.
Hosts typically have certain defenses against these types of viruses. Endogenous deaminases have been known to edit the RNA or DNA of pathogens to defend the host against the pathogen. In mammals, adenosine deaminases acting on RNAs (also called ADARs) and apolipoprotein B mRNA editing enzymes (APOBECs) exist.
These act on RNAs and DNAs, where they deaminate adenines into inosines and cytosines into uracils for ADARs and APOBECs, respectively. ADARs can act directly on the viral +ssRNA or indirectly by editing the host’s transcripts, which in turn modifies the cellular response. APOBECs typically target DNA intermediates directly or by interfering with the reverse transcription from RNA to DNA.
COVID-19 as a +ssRNA virus
Like other coronaviruses, SARS-CoV-2 is believed to be a +ssRNA virus. While much study remains to be done on COVID-19, there are some signs that human host molecules attempt to restrict the spread of the virus by editing their RNA through the use of ADARs and APOBECs.
The few studies done have found low levels of editing, but some have found that parts of the cellular transcripts have been highly edited by ADARs. APOBEC editing has been observed, which is impressive given that APOBEC editing is rarely detected. There is a bias for APOBEC to edit positive sense strands, which may then affect the entire viral genome than if a negative-sense strand was edited.
The full effect of this editing and the nature of the +ssRNA virus genome is still unclear. As mentioned, +ssRNA viruses are compact and compare only the necessary genetic information, which can be detrimental for the virus if there is editing occurring. However, while editing can cause the demise of a virus, it can also aid in its evolution.
The effect of these enzymes can be of huge clinical importance for COVID-19. For one, a sizable amount of the Chinese population has a mutation in certain APOBEC enzymes, which may influence the spread of the virus.
However, understanding how these enzymes are mutating the +ssRNA viral genome of COVID-19 can also potentially expose regions of the virus that can be used for therapeutic targets.