SARS-CoV-2: lessons from both the history of medicine and from the biological behavior of other well-known viruses

Abstract

SARS-CoV-2 is the etiological agent of the current pandemic worldwide and its associated disease COVID-19. In this review, we have analyzed SARS-CoV-2 characteristics and those ones of other well-known RNA viruses viz. HIV, HCV and Influenza viruses, collecting their historical data, clinical manifestations and pathogenetic mechanisms. The aim of the work is obtaining useful insights and lessons for a better understanding of SARS-CoV-2. These pathogens present a distinct mode of transmission, as SARS-CoV-2 and Influenza viruses are airborne, whereas HIV and HCV are bloodborne. However, these viruses exhibit some potential similar clinical manifestations and pathogenetic mechanisms and their understanding may contribute to establishing preventive measures and new therapies against SARS-CoV-2.

Keywords: COVID-19; SARS-CoV-2 pandemic; infectious diseases; pathogenesis; treatment.

Figure 1.. SARS-CoV-2 genome consists of a positive 5’-capped and 3’-polyadenylated ssRNA.

The viral genome sequence is approximately 30,000 bases in length. OFR1a and OFR1b genes are located on the 5’-end and codify two long polypeptides, defined as pp1a and pp1ab, respectively. These polypeptides are cleaved into 16 Nsps (not shown), from Nsps 1 to Nsps 16, such as some transmembrane domains, including Nsp4 and Nsp6 (see text) as well as Nsp12 Pol/RdRp. This enzyme is needed for efficient replication and transcription of the viral RNA genome. Furthermore, SARS-CoV-2 genome on 3’-terminus encodes four structural proteins, the nucleocapsid (N) protein, the matrix (M) protein, the small envelope (E) protein and the spike (S) glycoprotein and also some accessory proteins, like ORF 3a, 3 b, 6, 7a, 7b, 8, 9b, 10 and 14. Nsp: Nonstructural protein; OFR: Open-reading frame; Pol/RdRp: RNA-dependent RNA polymerase.

Figure 2.. HIV consists of two copies of positive-sense ssRNA, housed in a conical capsid.

HIV genome is composed by at least nine genes, defined gag, pol, env, tat, rev, nef, vif, vpr, vpu, encoding 19 proteins and two LTR regions at their 5′- and 3′-ends. Gag, pol and env codify structural proteins, which are incorporated into the new virions. Env encodes a precursor glycoprotein (gp160), which is cleaved into two parts, defined gp120 and gp41, by a cellular protease. Three molecules of gp120 and three of gp41 form a structure anchoring to the viral envelope. This apparatus allows gp120 to interact with specific receptors on target cells, such as CD4. The Gag (group-specific antigen) gene encodes the information for the synthesis of a 55-kDa polyprotein. This molecule is cut into several proteins after viral budding, including MA, CA, NC, spacer p1, spacer p2 and p6 domain. The pol gene encodes the enzymatic PR, RT and IN. Tat, rev, nef, vif, vpr and vpu represent regulatory genes and express proteins, modulating and regulating viral infectivity and replication and affecting the HIV ability to induce disease in the infected host (see text). CA: Capsid; IN: Integrase; LTR: Long terminal repeat; MA: Matrix; NC: Nucleocapsid; PR: Proteins protease; RT: Reverse transcriptase.

Figure 3.. HCV consists of a ssRNA genome, approximately 9.6 kb in length.

The viral genome includes a single ORF codifyng a polyprotein precursor of about 3010 aminoacids in length and 5′- and 3′-UTRs at both ends. Polyprotein cleavage generates mature structural- (core, E1 and E2) and nonstructural (NS1 or p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B) proteins. Core (C) protein is involved in the development of viral nucleocapsid structure and by the envelope glycoproteins; E1 and E2 are detectable on cell membrane; NS1or p7 is a short membrane protein; NS2 is a transmembrane protein; NS3 protein has serine protease- and NTPase/helicase activity; NS4A protein has a double function: cofactor for NS3 protein, its binding to NS3 increase its activity with a more efficient process of cleavage; modulation of NS5A phosphorylation; NS5A with unknown function; NS5B is the RdRp. ORF: Open-reading frame; RdRp: RNA-dependent RNA polymerase; UTR: Untranslated region.

Figure 4.. Representation of influenza virus genome.

Humans may be infected by influenza viruses type A, B & C. They differ in their organization, but only the A and B ones cause important clinical manifestations in mankind. Type A is considered as a paradigm. Influenza virus genome is about 13.5 kb in length, consists of a ssRNA with negative polarity (-) ssRNA and includes eight ssRNA segments. Each of these elements is separately enclosed in vRNPs. The 5′- and 3′-termini of viral RNA are associated with RdRp with multiple copies of NP. The influenza virus genome is composed of 11 proteins (HA, NA, NP, M1, M2, NS1, NS2 or NEP, PA, PB1, PB1-F2, PB2). The RNA polymerase of the influenza virus consists of three subunits, such as PB1, PB2 and PA, codified by three genes in influenza A and B viruses. A matrix consisting of M1 protein includes the virion core and it is surrounded by an external lipid envelope, where three integral glycoproteins, such as M2 (an ion channel), HA and NA are embedded. HA and NA are used to classify the different serotypes of influenza A viruses. Additional influenza virus proteins include the accessory protein PB1–F2, displaying proapoptotic activity, NS1 protein with anti-IFN-β function and promoting of viral replication, NEP (or NS2) nuclear export of viral ribonucleoproteins. HA: Hemagglutinin; NA: Neuraminidase; NP: Nucleoprotein; PA: Polymerase acidic; PB1: Polymerase basic 1; RdRp: RNA-dependent RNA polymerase; vRNP: Viral ribonucleoprotein complex.