11. Viral Genomes, Replication Strategies, and Subviral Agents: Study Notes

Size and Structure of Viral Genomes

Classification of Viral Genomes

Viruses are classified based on the nature and structure of their genomes, which determines their replication strategies and transcription mechanisms.

• Class I & VII: Double-stranded DNA (dsDNA) viruses (e.g., Hepatitis B virus)

• Class II: Single-stranded DNA (ssDNA) viruses (e.g., Parvovirus)

• Class III: Double-stranded RNA (dsRNA) viruses (e.g., Rotavirus)

• Class IV: Positive-sense single-stranded RNA (+ssRNA) viruses (e.g., Poliovirus, Coronaviruses)

• Class V: Negative-sense single-stranded RNA (−ssRNA) viruses (e.g., Influenza, Rabies virus)

• Class VI: Retroviruses (RNA genome, reverse transcribed to DNA; e.g., HIV)

Key Point: The genome type determines the pathway to mRNA synthesis, which is essential for viral protein production.

DNA Viruses

• Class I: dsDNA viruses transcribe mRNA directly from DNA.

• Class II: ssDNA viruses synthesize a complementary strand to form dsDNA, then transcribe mRNA.

• Class VII: dsDNA viruses replicate through an RNA intermediate using reverse transcriptase.

RNA Viruses

• Class III: dsRNA viruses transcribe mRNA from the negative strand.

• Class IV: +ssRNA viruses use their genome directly as mRNA.

• Class V: −ssRNA viruses synthesize mRNA from their genome using RNA replicase.

• Class VI: Retroviruses reverse transcribe RNA to DNA, then transcribe mRNA from DNA.

Summary Table: Baltimore Classification of Viruses

Class	Genome Type	Example	mRNA Synthesis
I	dsDNA	Adenovirus	Transcription from DNA
II	ssDNA	Parvovirus	Complementary strand synthesis, then transcription
III	dsRNA	Rotavirus	Transcription from negative strand
IV	+ssRNA	Poliovirus	Genome serves as mRNA
V	−ssRNA	Influenza virus	Transcription by RNA replicase
VI	ssRNA (RT)	HIV	Reverse transcription to DNA, then transcription
VII	dsDNA (RT)	Hepadnavirus	Reverse transcription via RNA intermediate

Double-Stranded DNA Animal Viruses

Unusual Replication Strategies

Some dsDNA animal viruses employ unique replication mechanisms that distinguish them from typical cellular DNA replication.

• Pox viruses: Replicate in the cytoplasm, carry their own transcription machinery.

• Adenoviruses: Replicate in the nucleus, can induce cancer.

Oncogenic Potential

• Polyomavirus SV40: Can induce tumors in nonpermissive hosts.

• Herpesviruses: Some members are associated with cancer (e.g., Epstein-Barr virus).

Replication Through RNA Intermediate

• Hepadnavirus: Uses reverse transcription during replication (e.g., Hepatitis B virus).

Uniquely Replicating DNA Animal Viruses

Pox Viruses

Poxviruses are among the largest and most complex animal viruses, with a unique replication cycle.

• Replication: Occurs entirely in the cytoplasm; virus encodes its own DNA and RNA polymerases.

• Historical Importance: Smallpox eradication is a major achievement in medical history.

• Medical Importance: Includes smallpox, monkeypox, cowpox.

Adenoviruses

Adenoviruses replicate their DNA in the nucleus and avoid the synthesis of a lagging strand by using a unique mechanism involving a protein primer.

• Replication: Linear DNA genome; replication initiates at both ends, forming a panhandle structure.

• Medical Importance: Can cause respiratory infections and are used in gene therapy vectors.

Polyomavirus and Tumor Induction

Host Cell Permissivity

• Permissive host cells: Virus replicates, new virions are produced, and host cell is lysed.

• Nonpermissive host cells: Viral DNA integrates into host genome (analogous to prophage), potentially leading to tumor formation.

Herpesvirus Replication

Replication Events

Herpes simplex virus replication involves the production of three classes of mRNA, each encoding different sets of proteins required for the viral life cycle.

• Immediate early proteins: Regulatory functions.

• Delayed early proteins: DNA replication enzymes.

• Late proteins: Structural components of the virion.

Positive-Strand RNA Animal Viruses

Replication Strategy

Positive-strand RNA viruses use their genome directly as mRNA, but replication requires synthesis of a negative-strand RNA intermediate.

• Examples: Poliovirus, Coronaviruses, Rhinoviruses, Hepatitis A virus, Flaviviruses.

Poliovirus

• Translation: Viral RNA is translated into a single polyprotein, which is then cleaved into functional proteins.

• Polyprotein: A large precursor protein that is processed into ~20 smaller proteins.

Coronaviruses

• Diseases: Cause respiratory infections, including SARS.

• Replication: Complex replication cycle involving synthesis of subgenomic RNAs.

Comparison: Poliovirus vs. Coronavirus Replication

Feature	Poliovirus	Coronavirus
Genome	+ssRNA	+ssRNA
Translation	Single polyprotein	Multiple subgenomic RNAs
Structure	Icosahedral	Helical, enveloped
Tail	No	Present (in some)

Negative-Strand RNA Animal Viruses

Replication Strategy

Negative-strand RNA viruses have genomes complementary to mRNA and require an RNA-dependent RNA polymerase (RNA replicase) to synthesize mRNA.

• Only infect Eukarya.

• Examples: Rhabdoviruses (Rabies), Orthomyxoviruses (Influenza), Paramyxoviruses (Measles, Mumps), Filoviruses (Ebola).

Rabies Virus

• Structure: Bullet-shaped, enveloped, helical nucleocapsid containing several enzymes.

• Replication: Viral RNA polymerase transcribes mRNA from the negative-strand genome.

Influenza Virus

• Structure: Enveloped, pleomorphic, segmented genome.

• Surface Proteins: Hemagglutinin binds sialic acid on host cells; Neuraminidase breaks down sialic acid component of host membrane.

Mechanisms to Evade the Immune System

• Antigenic drift: Subtle changes in neuraminidase and hemagglutinin proteins due to mutations.

• Antigenic shift: Reassortment of RNA segments from different viral strains infecting the same cell, generating new surface protein combinations.

Retroviruses

Replication Strategy

Retroviruses, such as HIV, are enveloped viruses with RNA genomes. They use reverse transcriptase to convert their RNA genome into DNA, which integrates into the host genome.

• Key Enzyme: Reverse transcriptase

• Replication Steps: RNA → DNA → Integration into host genome → Transcription of viral mRNA

Subviral Agents: Prions

Prions: Infectious Proteins

Prions are misfolded proteins that cause transmissible spongiform encephalopathies in animals and humans.

• Gene: Prnp encodes the normal prion protein (PrPC).

• Pathology: Misfolded prion protein (PrPSc) induces misfolding in normal proteins, leading to aggregation, insolubility, and resistance to proteases.

• Symptoms: Neurological decline, spongiform changes in brain tissue.

Major Prion Diseases

• Scrapie (sheep)

• Bovine spongiform encephalopathy (cattle)

• Chronic wasting disease (deer, elk)

• Creutzfeldt-Jakob Disease (CJD; humans)

• Kuru (humans)

• Fatal familial insomnia (humans)

Additional info: Prion diseases are invariably fatal and currently untreatable. Transmission can occur via ingestion, inheritance, or sporadic mutation.