Medical Pharmacology Chapter 36:  Antiviral Drugs

• Viral Genome and Virus Classification continued

  • Genomic organization and replication characteristics such as:¹

    • Gene order¹

      • Gene order is often highly conserved.^2,3

      • In the case of coronaviruses, which cause respiratory and enteric disease in many animals, this conservation a gene order is noteworthy in view of the high-frequency recombination.

        • Coronaviruses account for about one-third of colds in humans with symptoms similar to those of rhinoviruses.

          •  

            Coronaviruses

            CDC/ Dr. Fred Murphy. Attribution: Centers for Disease Control and Prevention Health Image Library "Coronaviruses are a group of viruses that have a halo, or crown-like (corona) appearance when viewed under an electron microscope. The coronavirus is now recognized as the etiologic agent of the 2003 SARS outbreak. http://en.wikipedia.org/wiki/Coronavirus#mediaviewer/File:Coronaviruses_004_lores.jpg

      • Furthermore, genes can be in the experimental setting artificially reordered without influencing viral replication.

        Sometimes accessory or group-specific genes may be interspersed between these structural protein genes.

        • Some accessory genes may affect pathogenesis including inhibition of interferon-regulated gene expression.

      • Coronaviruses are the largest of all of the RNA viruses and exhibit a single-stranded positive sense genome.^2,3

        • The viral polymerase (pol) is located at the 5' N-terminal and is followed by four structure genes common to all coronaviruses.

          • These are:

            • Spike protein (S) gene

            • Envelope protein (E) gene

            • Membrane protein (M) gene and the

            • Nucleocapsid protein (N) gene.

            •  

              Coronavirus Proteins³

          • The first gene from the 5' end, the polymerase, pol gene, accounts for about two thirds of the viral genome and is translated into polyproteins which are later cleaved by viral proteinases into at least 16 different proteins associated with genomic replication.

          • The other one third of the genome codes for structural proteins, may start with the hemagglutinin-esterase (HE) gene if the coronavirus incorporated it from a paramyxovirus, and then followed by the genes noted above.

            • That is, the hemagglutinin-esterase gene, if present, would have been inserted between the pol gene and the structural genes.

    • Number and position of open reading frames

      • An open reading frame (ORF) is that part of the reading frame containing no stop codons.

        • Nucleotide inserts following the start codon are responsible for "frameshift mutations" and cause stop codon dislocation in addition to other effects.

      • For example, in the case of hepatitis B virus four open reading frames have been characterized.

        • These frames are responsible for encoding seven polypeptides.

        • In particular, these open reading frames code for virion surface and core structural proteins, a transcriptional transactivator as well as a large polymerase protein which exhibits DNA polymerase, reverse transcriptase as well as RNase H enzymatic activity.

    • Replication strategies such as transcription patterns and translation

    • Cellular localization for protein accumulation, along with virion assembly and release.^2,3

    • Gene order is also conserved among different paramyxoviruses and rhabdoviruses, although some paramyxoviruses have additional genes.⁴

      • Moreover, at the junction between genes is a set of highly conserved intergenic sequences which regulate transcription termination, polyadenylation and reinitiation.

    • Also, gene order in filoviruses appear similar to those of parramyxoviruses and rhabdoviruses.⁵

  • Other virus classification approaches:¹

    • Virion protein characteristics

    • Antigenic characteristics

    • Molecular and physiochemical virion properties

    • Biological properties relating to interactions between the virus and host cells.¹