Introduction to Adenovirus Vectors

Adenovirus vectors are developed from double stranded DNA viruses that belong to the Adenoviridae family. When adenoviruses infect a host cell, their genetic material (DNA) is inserted into the host cell. However, it is not incorporated into the host’s genome. Instead, it is left free in the nucleus in the form of an extrachromosomal gene segment, which is also known as an episome. The information in this episomal DNA molecule is transcribed and translated in a similar manner as any other gene; however, the episomes themselves are not passed on to daughter cells post replication.

As compared to retroviruses, adenovirus are capable of infecting a broader variety of cells, including those that have a comparatively slow rate of cell division, such as lungs cells. The adenovirus genome comprises of multiple genes that are transcribed at different time points in the viral replication cycle. Genes transcribed early in the viral replication cycle are the E1, E2, E3 and E4 genes. Brief descriptions on their gene products and functions are provided below:

  • The E1 gene products, E1A and E1B, are involved in the replication of the virus.
  • E2 proteins provide the machinery for viral DNA replication and facilitate transcription of late genes.
  • Most of the E3 proteins are involved in modulating the host’s immune response.
  • E4 gene products are involved in the metabolism of virus messenger RNA (mRNA), promotion of viral DNA replication and in shutting-off of host protein synthesis.

Adenovirus vectors used in gene therapies lack the E1 gene. This gene is intentionally deleted in order to prevent viral replication. The E3 gene is also deleted in several cases in order to accommodate the therapeutic gene.

 

Adenovirus Advantages

Adenovirus vectors are considered among the most promising vectors for use in gene therapy. They are used for gene delivery for the treatment of various indications and are second only to retroviruses. Some of the advantages of these viral vectors are as follows:

  • Adenovirus vectors have a high transduction efficiency for dividing and non-dividing cells.
  • In addition, they have been shown to facilitate a high level of gene expression. However, since the transgene introduced into a host via an adenoviral vector is not integrated into the genome, the expression of the therapeutic gene is transient and lasts only for a small period of time.
  • Transgenes introduced via adenoviral vectors exist independently within the host cell nucleus as episomes. Their extrachromosomal location prevents germline gene transfer and also eliminates the risk of cancer due to insertional mutagenesis.
  • Adenovirus vectors can be produced at high titres.

These vectors are known to accommodate reasonably large transgenes (~7.5 kb).

 

Adenoviruses Limitations

The major drawbacks of using adenoviruses as vectors in gene therapy are as follows:

  • Adenoviruses are known to cause respiratory infections in humans. Severe inflammatory reactions have been reported in many clinical trials involving the use of adenoviral vectors.
  • Since these viruses lack an envelope, it is difficult to target adenoviruses to specific cells. Moreover, the ubiquitous nature of adenoviral receptors results in the uptake of these viruses by all cells types.