How SARS-CoV-2 escapes and suppresses the immune system (part 3)

This is the third article in a 15-part series titled “Relevance of SARS-CoV-2 Immune Suppression to Understanding and Controlling the Covid-19 Pandemic”, which will explore an underestimated but very important aspect of SARS-CoV-2 replication. . The ability of SARS-CoV-2 to delay, evade, and suppress the immune system has many implications for drugs, vaccines, and other aspects of our response to the pandemic. The first series of plays in this series is intended for a general audience; the second, for the medical community; and the third and final set, for biomedical researchers seeking a deeper understanding of variants, how they are generated, and what we might do to control them. Read the first part and second part.

A complex genome and replication strategy offers many new opportunities to develop drugs that prevent and treat SARS-CoV-2 infections.

The SARS-CoV-2 genome is one of the largest of all RNA viruses. On either side of the sequence are 5 primary regions and 3 primary untranslated regions, necessary to make new copies of the virus genome and initiate the synthesis of messenger RNA. Untranslated regions also contribute to the control of viral replication and the synthesis and translation of messenger RNA.

SARS-CoV-2 encodes 30 proteins. A set of 16 proteins, referred to as the NSP1-16 non-structural genes, are encoded by the first two-thirds of the genome. Upon infection, the full length viral RNA – which closely resembles cellular messenger RNA with a 5 prime cap and polyadenylate tail – serves as a template for the synthesis of these 16 proteins. Together, these early proteins create the intracellular conditions for replication and transcription.

The NSP proteins are originally made up of long polypeptides, with Orf1a encoding the NSP1-10 proteins and an extension, Orf1ab, encoding the 16 NSPs. Individual NSP proteins are cleaved from these precursors by the actions of two proteases, one specified by NSP3 and the other by NSP5.

The virus also codes for the four proteins of the infectious viral particle: the S protein which forms the surface peak, the E and M proteins integrated into the viral membrane and N, the nucleocapsid protein, which forms a complex with the genome. viral (Figure 3).

Interspersed among the structural genes are accessory genes designed as open reading frame proteins 3-10 (Orfs 3-10).

SARS-CoV-2 is a member of the nidovirus family, so called because of their unique means of producing 3 major terminal messenger RNAs. The messenger RNAs of the structural proteins and the 3 primary Orf proteins are made from a nested set of transcripts. The 3 main messenger RNAs are made up of subgenomic fragments, each serving as a separate replicon, resembling mini-genomes.

The synthesis of the messenger RNA of the first 3 genes begins with the transcription of the positive genome, creating a nested set of partial negative strand copies that contain both the original first 5 and first 3 untranslated terminal sequences. The transcription of a negative strand messenger RNA temple is truncated at the level of transcriptional regulatory sequences (TRS), followed by a jump to the untranslated prime region. The negative strand is then copied to produce a positive strand. Each subgenomic replicon serves as a template to produce positive strand messenger RNAs via a process akin to the production of full genomic RNA (Figure 4).

We need to understand the great complexity of the viral genome and proteins both to understand the disease and how to counteract it. As will become clear, many viral genes contribute to the virus’s ability to escape the immune system early on, allowing the virus to enter and escape before it is detected. The illness that occurs two to three weeks later is likely due to an immune system disruption that occurs earlier.

Detailed knowledge of how the virus exactly works is essential for the development of antiviral drugs that can be used alone or in combination to prevent and treat infections. We are still at an early stage of our understanding. We only know enough to know that we need to know a lot more. We desperately need a well-funded and highly targeted global effort to develop the detailed knowledge we need to create the next round of safe and effective antiviral drugs.

The virus’s complex genome and replication strategy also suggest that there are many ways the virus can respond to immune pressure and public health containment strategies. Current efforts focus almost exclusively on interpreting viral variation in terms of changes in spike protection function. Evidence is starting to emerge suggesting that increases in replication efficiency and immune suppression also contribute to increased transmission and virulence of SARS-CoV-2 variants. This unique means of producing messenger RNA may offer a selective advantage over many other RNA viruses which must produce all of their viral proteins from a single messenger RNA.

I suspect that this strategy allows the virus to preferentially amplify the first 3 messenger RNAs in response to selective pressure, as was recently documented for the Alpha variant. As we will see in the next article in this series, the preferential amplification of messenger RNA contributes to increased immune suppression by the Alpha variant.