Medically Important Viruses

Classification of Medically Important Viruses

• Virus classification relies on chemical and morphologic characteristics.
• The two main viral components used for classification are nucleic acid and the capsid.
• Nucleic acid is classified by its molecular weight and structure
• Capsid is classified by its size, symmetry, and whether it is enveloped

Viral Growth Curve

• Illustrates the quantity of virus produced over time post-infection.
• A single virion infecting a cell can produce hundreds more within approximately 10 hours.
• The viral growth cycle duration varies, bacterial viruses take minutes, human viruses take hours.
• The eclipse period is the time when no virus is detectable inside the cell.
• The eclipse period concludes upon the appearance of the virus.
• The latent period spans from the start of infection until the virus appears extracellularly.
• Viral infection starts with one particle and ends with the production of hundreds, a replication method unique to viruses.

Viral Replication Cycle

• Begins with attachment and penetration of the parental virion to the host cell.
• Uncoating of the viral genome occurs
• Early viral mRNA synthesis is performed
• Early viral protein synthesis
• Viral genome replicates
• Late viral mRNA synthesis
• Late viral protein synthesis
• Progeny virion assembly
• Virion release from the cell

Attachment, Penetration, and Uncoating

• Virion surface proteins bind weakly via noncovalent bonds to specific receptor proteins on the cell surface.
• Attachment specificity determines the virus's host range.
• Organ specificity is determined by receptor interaction.
• Viruses penetrate cells by being engulfed into a pinocytotic vesicle, which begins the uncoating process.
• A low pH within the vesicle promotes uncoating.
• Vesicle rupture or viral fusion deposits the virus's inner core into the cytoplasm

Cell Surface Receptors for Viruses

• Receptors are proteins with other functions in the cell's life
• CD4 protein is an HIV receptor involved in class 2 MHC protein binding for T cell activation.
• Bacteriophages use unique mechanisms to enter bacteria without counterparts in human, animal, or plant viruses.
• T group bacteriophages use tail fibers and lysozyme to infect E. coli by degrading the cell wall.
• The tail sheath contracts; then viral DNA enters through the core while capsid proteins stay outside.

Viral Nucleic Acids

• Viruses are infectious in cell culture, but not all purified viral genomes are.
• Infectious nucleic acid is purified viral DNA or RNA without protein that results in complete viral particles.
• Infectious nucleic acid can bypass host range specificity, a function of viral protein-cell receptor interaction.
• Only some viruses yield infectious nucleic acid.

Gene Expression and Genome Replication

• mRNA synthesis is the first step, after which pathways diverge depending on the nucleic acid type and cell location.
• DNA viruses (except poxviruses) replicate in the nucleus using host cell DNA-dependent RNA polymerase to synthesize mRNA.
• DNA viruses usually use DNA, except parvoviruses.
• DNA viruses possess their own polymerase for genome replication, unlike the host cell, but some parvoviruses are an exception
• RNA viruses replicate entirely in the cytoplasm, except retroviruses and influenza viruses, which have nuclear steps.
• RNA viruses use single-stranded RNA, except for members of the reovirus family.

RNA Polarity

• Positive polarity RNA is an RNA with the same base sequence as the mRNA.
• Negative polarity RNA has a base sequence that is complementary to the mRNA.
• Four groups of RNA viruses use varied mRNA synthesis strategies.

mRNA Synthesis Strategies for RNA Viruses

• Some use single-stranded RNA of positive polarity as genetic material to be directly used as mRNA
• Some use a single-stranded RNA of negative polarity needing transcription and requiring their own RNA-dependent RNA polymerase because cells can't use RNA as a template
• Some have double-stranded RNA requiring other RNA and enzymes in order to transcribe into mRNA
• Some use single-stranded RNA of positive polarity which is transcribed into double-stranded DNA by the RNA-dependent DNA polymerase, with the DNA then transcribed into viral mRNA via the regular host cell RNA polymerase (polymerase II).

Assembly and Release

• Progeny particles form as viral nucleic acids are packaged inside capsid proteins.
• Assembly steps are imprecise and only partially understood; some can assemble with purified RNA and protein.
• Budding occurs when enveloped viruses acquire lipoproteins for their envelope from the cell membrane.

Size and Shape

• Virus sizes range from 20–300 nm in diameter.
• They have complex structures of precise geometric symmetry.
• Virus shape relies on the arrangement of capsid's repeating subunits

Viral Nucleic Acids

• The viral genome is located internally and can be single- or double-stranded DNA or RNA.
• Nucleic acid is linear or circular
• DNA exists as a single molecule, while RNA can be a single molecule or in pieces.
• Viruses usually contain one genome copy (haploid), except retroviruses, which have two (diploid).

Viral Capsid and Symmetry

• The capsid is a protein coat surrounding nucleic acid, made of subunits called capsomers.
• The nucleocapsid refers to the combined structure of the nucleic acid genome and the capsid proteins

Viral Proteins

• Outer capsid proteins protect genetic material.
• Surface proteins attach to host cell receptors, determining specificity.
• Surface proteins are antibody targets and neutralize viral replication.
• Viruses may have internal proteins, namely DNA or RNA polymerases.
• Antigenic variants evade host defenses.
• Antibodies that neutralize one serotype do not neutralize others.

Viral Envelope

• It is a lipoprotein membrane made of host cell-derived lipid and virus-specific protein.
• It contains antigens that elicit host immune responses.
• Enveloped viruses are heat, drying, detergent, and lipid solvent sensitive.
• Viruses transmitted via the fecal-oral route lack envelopes.

Atypical Viruslike Agents

• Defective viruses needs a "helper" to replicate due to genetic material mutation or deletion.
• Pseudovirions contain host cell DNA instead of viral DNA, being formed when host cell DNA is fragmented and packaged, they can infect cells but not replicate.
• Viroids are molecules of circular RNA without a protein coat or envelope that do code code for any protein and only cause plant diseases
• Prions are infectious protein particles without nucleic acid that cause transmissible spongiform encephalopathies.

Mutations

• Viral DNA and RNA mutations result from base substitution, deletion, and frameshift.
• The use of mutations is most important in live, attenuated vaccines.
• Attenuated mutants display loss of pathogenicity but retain antigenicity.
• Immunity is induced here without causing disease.
• Antigenic variants occur in influenza viruses due to surface protein alteration and are no longer inhibited by preexisting antibodies
• Drug-resistant mutants are insensitive to antiviral drugs, because the target viral enzyme is modified.

Viral Interactions

• Three events occur when two genetically distinct viruses infect one cell: recombination, complementation, and phenotypic mixing.
• Recombination is the exchange of genes between chromosomes based on crossing over and sequence homology which is demonstrated in DNA viruses; rare in RNA viruses.
• Reassortment in viruses such as influenza results in a high frequency of gene exchange.
• The reassortment of influenza virus RNA segments causes major antigenic changes and recurrent epidemics.
• Complementation happens when infected viruses have nonfunctional protein-resulting mutations.
• Helper viruses complement defective viruses, like hepatitis B providing antigens for hepatitis delta virus.
• Phenotypic mixing occurs when one virus's genome is coated with surface proteins from another.
• A phenotypically mixed virus infects cells depending on its protein coat.

Gene Therapy and Recombinant Vaccines

• Viruses serve as genetic vectors in gene therapy and recombinant vaccines.
• Gene therapy uses vectors to deliver functional genes to patients with genetic diseases.
• Recombinant vaccines use recombinant viruses to induce immunity to several diseases with one immunization.

Gene Therapy

• Vectors deliver genes encoding adenine deaminase in patients with immunodeficiencies resulting from a defective ADA gene
• Retroviruses are vectors, because DNA is integrated and efficiently expressed and can replace deficient genes.

Recombinant Vaccines

• Recombinant viral vaccines are genetically engineered to carry genes of other viruses.
• Large-genome viruses like vaccinia are candidates.
• A nonessential vaccinia gene is deleted, and a gene from another virus encoding the antigen that elicits neutralizing antibody is introduced.
• Recombinant vaccines are unavailable.