3.4 Genome replication and expression mechanisms

Viruses employ diverse strategies to replicate their genomes and express their genes. DNA viruses typically use host machinery in the nucleus, while RNA viruses rely on their own enzymes in the cytoplasm. Some viruses, like retroviruses, even convert their RNA to DNA.

Viral replication involves synthesizing new genetic material through various mechanisms. The process differs between DNA and RNA viruses, with each type using specific enzymes and strategies. Understanding these mechanisms is crucial for developing effective antiviral treatments and vaccines.

Viral Genome Replication Mechanisms

DNA and RNA Virus Replication Strategies

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• Viral genome replication synthesizes new copies of viral genetic material (DNA or RNA)
• DNA viruses typically replicate in host cell nucleus using host enzymes and viral proteins
• RNA viruses replicate in cytoplasm using virus-encoded RNA-dependent RNA polymerases (RdRp)
• Some RNA viruses (retroviruses) use reverse transcription to convert RNA to DNA before integration
• Replication involves forming complementary strands through semiconservative replication (DNA viruses) or complementary negative-sense RNA synthesis (RNA viruses)
• Replication strategies classified as conservative, semiconservative, or dispersive based on parental and new strand distribution
  • Conservative: Parental strands remain together, new strands form separate double helix
  • Semiconservative: Each new double helix contains one parental and one new strand
  • Dispersive: Fragments of parental and new DNA interspersed in new double helices
• Replication efficiency and fidelity impact viral fitness, evolution, and antiviral resistance development
  • High fidelity limits mutations but reduces adaptability
  • Low fidelity increases mutation rate, potentially yielding beneficial adaptations

Genome Replication Process

• DNA virus replication steps:
  1. Attachment to host DNA
  2. Unwinding of DNA by helicases
  3. Primer synthesis by primase
  4. DNA synthesis by DNA polymerase
  5. Removal of RNA primers
  6. Gap filling and ligation
• RNA virus replication steps:
  1. Uncoating of viral genome
  2. Translation of viral proteins (if +RNA)
  3. Synthesis of complementary -RNA strand
  4. Use of -RNA as template for +RNA synthesis
  5. Packaging of new genomes into virions
• Retroviruses employ unique replication strategy:
  1. Reverse transcription of RNA to DNA
  2. Integration of viral DNA into host genome
  3. Transcription of viral genes
  4. Translation of viral proteins
  5. Assembly and budding of new virions

Viral Enzymes in Genome Replication

Polymerases and Their Functions

• Viral polymerases catalyze synthesis of new nucleic acid strands during genome replication
• DNA-dependent DNA polymerases used by DNA viruses (Herpes simplex virus)
• RNA-dependent RNA polymerases employed by RNA viruses (Influenza virus)
• Reverse transcriptases convert RNA to DNA in retroviruses (HIV)
• Polymerase processivity determines length of nucleic acid synthesized before dissociation
  • High processivity enzymes (T7 DNA polymerase) synthesize long stretches without dissociating
  • Low processivity enzymes (Taq polymerase) dissociate more frequently
• Polymerase fidelity influences mutation rate and viral evolution
  • High fidelity polymerases (T7 DNA polymerase) make fewer errors
  • Low fidelity polymerases (Influenza virus RNA polymerase) generate more mutations

Helicases and Accessory Enzymes

• Viral helicases unwind double-stranded nucleic acids for replication
  • Use energy from ATP hydrolysis to break hydrogen bonds between base pairs
  • Examples include SV40 large T antigen and hepatitis C virus NS3 helicase
• Primases synthesize short RNA primers for DNA replication initiation
  • Often associated with helicases in enzyme complexes
  • Primase-helicase complexes found in bacteriophage T7 and herpes simplex virus
• Topoisomerases relieve DNA torsional stress during replication
  • Type I topoisomerases make single-strand breaks
  • Type II topoisomerases make double-strand breaks
  • Poxviruses encode their own topoisomerases for efficient genome replication

Transcription and Translation Strategies

DNA Virus Gene Expression

• DNA viruses utilize host cell transcription machinery to produce mRNA
• Temporal regulation of gene expression common in DNA viruses
  • Immediate early genes: Expressed first, often regulatory proteins
  • Early genes: Involved in genome replication
  • Late genes: Typically structural proteins for virion assembly
• Examples of DNA virus gene expression strategies:
  • Herpesviruses: Cascade of immediate early, early, and late gene expression
  • Adenoviruses: Complex splicing patterns generate multiple mRNAs from single transcripts

RNA Virus Gene Expression

• Positive-sense RNA genomes serve directly as mRNA for translation
  • Examples include poliovirus and hepatitis C virus
• Negative-sense RNA viruses synthesize complementary positive-sense RNA for translation
  • Examples include influenza virus and rabies virus
• Ambisense RNA viruses contain both positive and negative-sense RNA segments
  • Example: Arenaviruses
• Cap-snatching mechanism used by some viruses (Influenza)
  • Viral endonuclease cleaves host mRNA caps
  • Stolen caps used to prime viral mRNA synthesis
• Polyprotein production and processing in many RNA viruses
  • Single large protein cleaved by viral proteases into functional units
  • Examples include picornaviruses and flaviviruses

Viral Replication and Pathogenesis

Impact on Host Cells and Tissues

• Viral genome replication rate influences speed of viral spread
  • Rapid replication leads to faster progression of infection (Influenza)
  • Slow replication may result in persistent infections (Hepatitis B virus)
• Replication errors generate mutations affecting virulence and host range
  • Antigenic drift in influenza virus due to mutations in surface proteins
  • Host range expansion in avian influenza adapting to mammalian hosts
• Viral gene expression modulates host immune response
  • Epstein-Barr virus latent proteins inhibit apoptosis in infected B cells
  • HIV Nef protein downregulates CD4 and MHC class I molecules
• Hijacking host machinery causes cellular stress and dysfunction
  • Picornavirus infection shuts down host protein synthesis
  • Hepatitis C virus induces endoplasmic reticulum stress

Tissue Tropism and Disease Manifestation

• Viral genome replication in specific cell types determines tropism
  • HIV infects CD4+ T cells and macrophages, leading to immunodeficiency
  • Poliovirus replicates in motor neurons, causing paralysis
• Timing of viral gene expression influences infection course
  • Early genes in herpesviruses establish latency in neurons
  • Late genes in poxviruses produce structural proteins for virion assembly
• Persistent infections established through regulated replication
  • Hepatitis B virus maintains low-level replication in hepatocytes
  • Herpes simplex virus enters latency in sensory neurons

Antiviral Drug Targets in Viral Replication

Polymerase and Replication Complex Inhibitors

• Viral polymerases serve as prime targets due to essential role and structural differences from host enzymes
• Nucleoside and nucleotide analogs act as chain terminators or mutagens
  • Acyclovir inhibits herpes simplex virus DNA polymerase
  • Remdesivir targets RNA-dependent RNA polymerase of SARS-CoV-2
• Non-nucleoside inhibitors bind to allosteric sites on viral polymerases
  • Nevirapine inhibits HIV reverse transcriptase
• Helicase inhibitors prevent unwinding of viral genomes
  • Umifenovir (Arbidol) targets influenza virus helicase

Targeting Viral Gene Expression and Processing

• Protease inhibitors prevent polyprotein processing
  • Lopinavir inhibits HIV protease
  • Telaprevir targets hepatitis C virus NS3/4A protease
• Transcription inhibitors disrupt viral gene expression
  • Cidofovir inhibits cytomegalovirus DNA polymerase and immediate early gene transcription
• Compounds interfering with genome packaging or assembly
  • Bevirimat prevents HIV capsid maturation
• Combination therapies target multiple replication steps
  • HAART (Highly Active Antiretroviral Therapy) for HIV combines multiple drug classes
  • Direct-acting antiviral combinations for hepatitis C target different viral proteins