18.1 Viral vectors for gene delivery and expression

Viral vectors are modified viruses engineered to deliver genes to target cells. They exploit viruses' natural ability to infect and introduce genetic material into hosts. These vectors can carry foreign genes, are designed to be replication-defective, and express transgenes under specific promoters.

Different viral vectors have unique advantages and drawbacks. Adenoviral vectors offer high efficiency but elicit strong immune responses. AAV vectors provide long-term expression with low immunogenicity. Retroviral and lentiviral vectors integrate into the host genome, offering stable expression but carrying risks of insertional mutagenesis.

Viral vector characteristics for gene delivery

Structure and function of viral vectors

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• Modified viruses engineered to deliver genetic material to target cells
• Exploit natural ability of viruses to infect and introduce genetic material into host cells
• Carry foreign genes with varying capacities (few kilobases to over 150 kilobases)
• Designed to be replication-defective for safe gene delivery without causing viral infection
• Express transgenes under control of specific promoters for regulated or tissue-specific expression
• Some vectors (retroviruses, lentiviruses) integrate genetic material into host genome for long-term expression

Tropism and transduction efficiency

• Ability to infect specific cell types (tropism) varies among vector types
• Transduction efficiency differs between vector systems (adenoviral vectors offer high efficiency)
• Can infect dividing and/or non-dividing cells depending on vector type
• Packaging capacity impacts amount of genetic material that can be delivered
• Immunogenicity affects both efficiency of gene delivery and safety profile

Advantages vs disadvantages of viral vectors

Adenoviral and adeno-associated viral (AAV) vectors

• Adenoviral vectors:
  • High transduction efficiency
  • Infect both dividing and non-dividing cells
  • Elicit strong immune responses
  • Provide only transient gene expression
• AAV vectors:
  • Low immunogenicity
  • Provide long-term gene expression
  • Limited packaging capacity
  • May require high doses for efficient transduction

Retroviral and lentiviral vectors

• Retroviral vectors:
  • Integrate into host genome for stable gene expression
  • Limited to infecting dividing cells
  • Carry risk of insertional mutagenesis
• Lentiviral vectors:
  • Infect both dividing and non-dividing cells
  • Offer stable gene expression
  • Carry risk of insertional mutagenesis
  • Derived from HIV, raising safety concerns

Herpes simplex viral vectors and vector selection

• Herpes simplex viral vectors:
  • Large packaging capacity
  • Natural neurotropism suitable for nervous system gene delivery
  • May have cytotoxic effects
  • Provide only transient gene expression
• Vector selection depends on:
  • Target cell type
  • Desired duration of gene expression
  • Packaging capacity requirements
  • Safety considerations for specific application

Engineering viral vectors for gene delivery

Vector design and construction

• Remove pathogenic genes from viral genome
• Replace removed genes with desired therapeutic or experimental genes
• Select appropriate viral backbone based on target cell type and expression profile
• Provide essential viral genes for packaging and infection on separate plasmids
• Clone transgene of interest into transfer plasmid with necessary viral elements
• Select promoters for controlling transgene expression (constitutive, inducible, tissue-specific)

Vector production and quality control

• Transfect producer cells with transfer plasmid and helper plasmids
• Harvest and purify resulting viral particles
• Implement quality control measures:
  • Test for replication competence
  • Assess vector titer
  • Ensure safety and efficacy of engineered vectors

Choosing viral vectors for research or therapy

Target considerations and expression requirements

• Evaluate target cell type and tissue tropism of different vectors
• Assess desired duration of gene expression:
  • Long-term expression for genetic disorders
  • Transient expression for cancer therapy
• Consider size of transgene to be delivered and vector packaging capacity
• Examine immune status of recipient for potential pre-existing immunity

Delivery methods and safety considerations

• Evaluate route of administration (systemic vs local delivery)
• Assess safety profile:
  • Risk of insertional mutagenesis (retroviral and lentiviral vectors)
  • Potential for reversion to replication-competent forms
• Consider scalability and ease of production for research and therapeutic applications
• Evaluate potential for clinical translation and regulatory requirements