Viral Genomes, Replication Strategies, and Subviral Agents

Size and Structure of Viral Genomes

Overview of Viral Genome Classes

Viruses possess diverse genome types, which determine their replication and transcription strategies. The Baltimore classification system organizes viruses based on their genome type and the pathway to mRNA synthesis.

• Class I & VII: Double-stranded DNA (dsDNA) viruses

• Class II: Single-stranded DNA (ssDNA) viruses

• Class III: Double-stranded RNA (dsRNA) viruses

• Class IV: Positive-sense single-stranded RNA (+ssRNA) viruses

• Class V: Negative-sense single-stranded RNA (-ssRNA) viruses

• Class VI: Retroviruses (RNA genome, DNA intermediate)

Each class uses a distinct mechanism to generate mRNA for protein synthesis.

Class	Genome Type	Example	Pathway to mRNA
I	dsDNA	Herpesvirus	Transcription of DNA to mRNA
II	ssDNA	Parvovirus	Conversion to dsDNA, then transcription
III	dsRNA	Reovirus	Transcription of dsRNA to mRNA
IV	+ssRNA	Poliovirus	Genome serves directly as mRNA
V	-ssRNA	Influenza virus	Transcription by viral RNA replicase
VI	+ssRNA (retrovirus)	HIV	Reverse transcription to DNA, then transcription
VII	dsDNA (with RNA intermediate)	Hepadnavirus	Transcription to RNA, then reverse transcription

Double-Stranded DNA Animal Viruses

Unusual Replication Strategies

Some dsDNA animal viruses employ unique replication mechanisms and can have significant medical implications.

• Pox viruses: Replicate in the cytoplasm, are among the largest and most complex animal viruses, and have historical importance due to smallpox eradication.

• Adenoviruses: Replicate in the nucleus and avoid synthesis of a lagging strand by using a unique DNA replication strategy.

Oncogenic Potential

• Polyomavirus SV40 and Herpesviruses can induce cancer by integrating their DNA into host genomes.

Replication via RNA Intermediate

• Hepadnavirus: Replicates its DNA genome through an RNA intermediate using reverse transcriptase.

Uniquely Replicating DNA Animal Viruses

Pox Viruses

Pox viruses are notable for their size, complexity, and cytoplasmic replication. They played a major role in human history due to smallpox.

• Replicate entirely in the cytoplasm, unlike most DNA viruses.

• Medical importance: Smallpox eradication, vaccine development.

Adenoviruses

Adenoviruses use a distinctive DNA replication mechanism that avoids the need for lagging strand synthesis.

• Replication occurs in the nucleus.

• Uses a protein primer to initiate DNA synthesis.

Polyomavirus and Tumor Induction

Host Cell Permissivity

• Permissive host cells: Virus completes its replication cycle, producing new virions and lysing the host cell.

• Nonpermissive host cells: Viral DNA integrates into host DNA (similar to a prophage), potentially transforming the cell and leading to tumor formation.

Herpesvirus Replication

Replication Events

Herpes simplex virus replication involves the production of three classes of mRNA: immediate-early, early, and late, each encoding different sets of proteins for viral replication and assembly.

• Immediate-early: Regulatory proteins

• Early: Enzymes for DNA replication

• Late: Structural proteins

Positive-Strand RNA Animal Viruses

Replication Mechanism

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

• Genome is translated into a single polyprotein, which self-cleaves into ~20 functional proteins.

Coronaviruses

• Cause respiratory infections, including SARS.

• Replication involves synthesis of a negative-strand intermediate and production of multiple subgenomic mRNAs.

Comparison: Poliovirus vs. Coronavirus Replication

• Similarities: Both use RNA replicase to synthesize complementary strands, produce a poly(A) tail and 5' cap on mRNAs.

• Differences: Poliovirus produces a single polyprotein; coronaviruses produce multiple proteins from subgenomic mRNAs.

Negative-Strand RNA Animal Viruses

Replication Mechanism

Negative-strand RNA viruses have genomes complementary to mRNA and require a virion-associated RNA replicase to synthesize mRNA.

• Only infect Eukarya.

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

Rabies Virus

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

Influenza Virus

• Enveloped, pleomorphic, segmented genome.

• Surface proteins: Hemagglutinin (binds sialic acid), Neuraminidase (cleaves sialic acid).

Influenza Mechanisms to Evade the Immune System

Antigenic Drift

Gradual mutations in hemagglutinin and neuraminidase genes alter surface proteins, allowing the virus to evade immune detection.

Antigenic Shift

Reassortment of RNA segments from different viral strains infecting the same cell produces new combinations of surface proteins, potentially leading to pandemics.

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.

• Replication involves reverse transcription, integration, transcription, and assembly.

Subviral Agents: Prions

Prion Biology

Prions are infectious proteins that cause transmissible spongiform encephalopathies in animals. The host gene Prnp encodes the normal prion protein (PrPC), which can misfold into the disease-causing form (PrPSc).

• Misfolded prions are resistant to proteases, insoluble, and aggregate in neural tissue, causing neurological symptoms.

Major Prion Diseases

• Scrapie

• Bovine spongiform encephalopathy (BSE)

• Chronic wasting disease

• Creutzfeldt-Jakob Disease (CJD)

• Kuru

• Fatal familial insomnia