H101 virus

Adenovirus varieties have been explored extensively as a viral vector for gene therapy and also as an oncolytic virus.

Of the many different viruses being explored for oncolytic potential, an adenovirus was the first to be approved by a regulatory agency, the genetically modified H101 strain. It gained regulatory approval in 2005 from China's State Food and Drug Administration (SFDA) for the treatment of head and neck cancer.

Adenoviruses have so far been through three generations of development. Some of the strategies for modification of adenoviruses are described below.

For adenovirus replication to occur, the host cell must be induced into S phase by viral proteins interfering with cell cycle proteins. The adenoviral E1A gene is responsible for inactivation of several proteins, including retinoblastoma, allowing entry into S-phase. The adenovirus E1B55kDa gene cooperates with another adenoviral product, E4ORF6, to inactivate p53, thus preventing apoptosis. It was initially proposed that an adenovirus mutant lacking the E1B55kDa gene, dl1520 (ONYX-015), could replicate selectively in p53 deficient cells.

A conditionally replicative adenovirus (CRAd) with a 24 base pair deletion in the retinoblastoma-binding domain of the E1A protein (Ad5- Δ24E3), is unable to silence retinoblastoma, and therefore unable to induce S-phase in host cells. This restricts Ad5-Δ24E3 to replication only in proliferating cells, such as tumour cells.

The most commonly used group of adenoviruses is serotype 5 (Ad5), whose binding to host cells is initiated by interactions between the cellular coxsackie virus and adenovirus receptor (CAR), and the knob domain of the adenovirus coat protein trimer. CAR is necessary for adenovirus infection. Although expressed widely in epithelial cells, CAR expression in tumours is extremely variable, leading to resistance to Ad5 infection. Retargeting of Ad5 from CAR, to another receptor that is ubiquitously expressed on cancer cells, may overcome this resistance.

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