Viruses and Prions: Structure, Replication, and Clinical Relevance

Viruses and Prions

Introduction to Viruses

Viruses are nonliving, submicroscopic infectious agents that require a host cell to replicate. The study of viruses is known as virology. Viruses are extremely small (20–400 nm), acellular, and obligate intracellular pathogens. Approximately 70% of viruses that infect humans are also found in other animals.

Comparing Viruses, Prokaryotes, and Eukaryotes

Viruses differ fundamentally from prokaryotic and eukaryotic cells in structure, replication, and life cycle. They lack cellular organization and metabolic machinery, relying entirely on host cells for reproduction.

Diversity of Viral Structure and Genomes

Viruses can infect all domains of life. Two major groups are bacteriophages (infect bacteria) and animal viruses (infect animals and humans). The infectious particle is called a virion, consisting of a protective protein capsid and genetic material (DNA or RNA).

Viral Capsids

• Capsid: Protein shell protecting the genome, made of capsomere subunits.

• Most animal viruses have helical (hollow tube) or icosahedral (polygonal) capsids. Deviations are termed complex capsids.

• Bacteriophages often have complex capsids with icosahedral symmetry and structures for genome injection.

Viral Envelopes

• Enveloped viruses possess a lipid-based envelope derived from the host cell membrane during budding.

• Naked viruses lack an envelope and are released by lysing the host cell.

• Animal viruses may be enveloped or naked; bacteriophages are always naked.

Viral Spikes (Peplomers)

• Spikes are glycoprotein extensions that facilitate attachment and entry into host cells.

• They bind specifically to host cell receptors, determining host range and tissue tropism.

• Influenza viruses have two key spikes: hemagglutinin (HA) and neuraminidase (NA).

Viral Genomes

Viral genomes are compact, usually encoding fewer than 300 genes for capsid proteins, replication enzymes, and structural factors. They may be DNA or RNA, single- or double-stranded, segmented or non-segmented, and circular or linear.

• dsDNA viruses: DNA is transcribed by host RNA polymerases; mRNA is translated into protein.

• ssDNA viruses: Converted to dsDNA before transcription.

• ssRNA (+): Genome acts as mRNA, directly translated by host ribosomes.

• ssRNA (–): Genome is complementary to mRNA; transcribed into mRNA by RNA-dependent RNA polymerases.

• Retroviruses: RNA genome is reverse transcribed into DNA, which integrates into the host genome.

• dsRNA viruses: Require RNA-dependent RNA polymerases for mRNA synthesis.

Viral Genome Evolution

• Viruses mutate rapidly due to quick replication and lack of proofreading in RNA polymerases.

• Mutations can be neutral, beneficial, or deleterious. Beneficial mutations may enhance infectivity, host range, or immune evasion.

• Reassortment: When two viral strains coinfect a cell, their genomes can mix, creating new strains.

Antigenic Drift and Shift

• Antigenic drift: Minor changes in viral antigens (e.g., influenza HA and NA spikes) due to mutations.

• Antigenic shift: Major genetic reassortment, leading to new viral subtypes and potential pandemics.

Viral Classification and Taxonomy

• Viruses are classified by nucleic acid type, capsid symmetry, envelope presence, and genome architecture.

• The International Committee on Taxonomy of Viruses (ICTV) sets naming conventions.

• Taxonomic ranks: Phylum, Order, Family, Genus, Species.

Medically Important DNA and RNA Virus Families

DNA and RNA viruses are grouped by genome type, capsid shape, and envelope status. Examples include:

• DNA viruses: Parvoviridae, Adenoviridae, Herpesviridae, Poxviridae, Hepadnaviridae, Papillomaviridae.

• RNA viruses: Picornaviridae, Orthomyxoviridae, Retroviridae, Coronaviridae, Flaviviridae, Rhabdoviridae, etc.

Host Range and Tropism

• Host range: The spectrum of species a virus can infect.

• Tropism: Specificity for certain tissues or cell types, determined by viral surface factors.

Viral Replication Strategies

Bacteriophage Replication

• Lytic cycle: Virus infects, replicates, and lyses the host cell.

• Lysogenic cycle: Viral genome integrates into host DNA as a prophage, replicates with the host, and may later enter the lytic cycle.

• Phage conversion: Prophages can confer new pathogenic traits to bacteria (e.g., toxin production).

Animal Virus Replication

Animal viruses follow six main steps: attachment, penetration, uncoating, replication, assembly, and release.

• Attachment: Naked viruses use capsid proteins; enveloped viruses use spikes.

• Penetration: Enveloped viruses enter by endocytosis or membrane fusion; naked viruses by endocytosis.

• Uncoating: Capsid is digested, releasing the genome.

• Replication and Assembly: Genome is replicated, proteins are synthesized, and new virions are assembled.

• Release: Enveloped viruses bud off; naked viruses lyse the host cell.

Persistent Viral Infections

• Acute infections: Rapid onset, short duration.

• Chronic infections: Continuous release of virions, slow disease progression (e.g., HIV forms a provirus).

• Latent infections: Intermittent flare-ups with periods of dormancy (e.g., herpesviruses).

Oncogenic Viruses

• Oncoviruses can cause cancer by promoting uncontrolled cell division or inhibiting cell death.

• Examples: Human papillomavirus (HPV), Human T-lymphotropic virus (HTLV).

Growing Viruses in the Laboratory

Bacteriophage Cultivation

• Grown using plaque assays on bacterial lawns; clear zones (plaques) indicate lysis.

• Plaque-forming units (PFUs) quantify viral particles.

Animal Virus Cultivation

• More challenging; often requires tissue culture, live animals, or embryonated eggs.

Viral Diagnostics

• Detection methods include identification of viral genetic material, proteins, or patient antibodies.

• Key qualities: specificity (no false positives) and sensitivity (no false negatives).

Agglutination Tests

• Use antibodies or antigens attached to beads; agglutination indicates a positive result.

Enzyme-Linked Immunosorbent Assays (ELISA)

• Detect antigens or antibodies via color change on a surface.

• Limitations: requires liquid samples, well-characterized antigens, and may miss new variants.

Nucleic Acid Detection

• Highly sensitive; uses PCR, sequencing, or fluorescent probes to detect viral DNA/RNA.

Antiviral Drugs and Vaccines

• Antivirals target steps in the viral life cycle but rarely cure infections.

• Vaccines are crucial for prevention, training the immune system to recognize viruses.

Drug Mechanisms

• Block attachment, penetration, uncoating (e.g., amantadine, rimantadine, docosanol).

• Block replication (e.g., nucleoside analogs, reverse transcriptase inhibitors like AZT).

• Block release (e.g., oseltamivir, zanamivir for influenza).

• Interferons boost host antiviral defenses.

Prions

• Prions are infectious proteins without genetic material, causing transmissible spongiform encephalopathies (TSEs).

• Examples: Creutzfeldt-Jakob disease, fatal familial insomnia, Gerstmann-Sträussler-Scheinker syndrome.

• Some neurodegenerative diseases (e.g., Alzheimer's, Parkinson's, ALS) exhibit prion-like features.