Cell Entry and Unusual Replication of SARS-CoV-2.

BACKGROUND: SARS-CoV-2 is the causative virus for the CoVID-19 pandemic that has frequently mutated to continue to infect and resist available vaccines. Emerging new variants of the virus have complicated notions of immunity conferred by vaccines versus immunity that results from infection. While we continue to progress from epidemic to endemic as a result of this collective immunity, the pandemic remains a morbid and mortal problem. OBJECTIVE: The SARS-CoV-2 virus has a very complex manner of replication. The spike protein, one of the four structural proteins of the encapsulated virus, is central to the ability of the virus to penetrate cells to replicate. The objective of this review is to summarize these complex features of viral replication. METHODS: A review of the recent literature was performed on the biology of SARS-CoV-2 infection from published work from PubMed and works reported to preprint servers, e.g., bioRxiv and medRxiv. RESULTS AND CONCLUSION: The complex molecular and cellular biology involved in SARS-CoV-2 replication and the origination of >30 proteins from a single open reading frame (ORF) have been summarized, as well as the structural biology of spike protein, a critical factor in the cellular entry of the virus, which is a necessary feature for it to replicate and cause disease.

Spike protein receptor-binding domains from SARS-CoV-2 variants of interest bind human ACE2 more tightly than the prototype spike protein.

Several SARS-CoV-2 variants of interest (VOI) have emerged since this virus was first identified as the etiologic agent responsible for COVID-19. Some of these variants have demonstrated differences in both virulence and transmissibility, as well as in evasion of immune responses in hosts vaccinated against the original strain of SARS-CoV-2. There remains a lack of definitive evidence that identifies the genetic elements that are responsible for the differences in transmissibility among these variants. One factor affecting transmissibility is the initial binding of the surface spike protein (SP) of SARS-CoV-2 to human angiotensin converting enzyme-2 (hACE2), the widely accepted receptor for SP. This step in the viral replication process is mediated by the receptor binding domain (RBD) of SP that is located on the surface of the virus. This current study was conducted with the aim of assessing potential differences in binding affinity between recombinant hACE2 and the RBDs of emergent SARS-CoV-2 WHO VOIs. Mutations that affect the binding affinity of SP play a dominant initial role in the infectivity of the virus.