Attenuation And Safety

A number of different mutations in the genome of replication-competent viruses attenuate their toxicity to normal cells. The gene 7134.5 exists as two copies in the HSV genome and is largely responsible for neurotoxicity. The 7134.5 gene product prevents the infected host cell from shutting off its cellular machinery, a normal host response to viral infection, and allows ongoing viral replication. A deletion in the 7134.5 gene therefore hinders viral replication, and has been shown to limit viral spread within the central nervous system (7). Another important gene for replication, UL39, encodes the enzyme ribonucleotide reductase (RR). This enzyme is essential for the reduction of ribonucleotides to deoxyribonucleotides, which form the DNA substrate pool (8). Ribonucleotide reductase therefore plays a critical role in viral DNA synthesis, and deletions in RR limit viral replication. Eukaryotic cells also produce a cellular variant

Fig. 1. HSV structure. (A) The viral envelope contains membrane-bound glycoproteins that aid in docking the virus and binding to receptors on the tumor cell membrane. (B) The proteinaceous tegument is released in the cytoplasm and guides the inner icosahedral capsid to the nucleus. (C) The capsid delivers the 152-kb double-stranded DNA viral genome to the nucleus.

Fig. 1. HSV structure. (A) The viral envelope contains membrane-bound glycoproteins that aid in docking the virus and binding to receptors on the tumor cell membrane. (B) The proteinaceous tegument is released in the cytoplasm and guides the inner icosahedral capsid to the nucleus. (C) The capsid delivers the 152-kb double-stranded DNA viral genome to the nucleus.

of RR during cell division. This cellular RR has significant sequence homology to that of viral RR and can be used to promote viral replication in dividing cells (9). Therefore, HSV with deletions in UL39 can only replicate in rapidly dividing cells, such as some cancer cells, which produce sufficiently high levels of exogenous, cellular RR (10).

Additional mutations in the viral genome allow the host to respond more vigorously to viral infection. The V47 gene normally functions to down-regulate MHC class I peptides on the surface of virally infected cells. This cloaks an infected cell from the host's immune system. A mutation in the V47 gene enables major histocompatability complex (MHC) class I peptide expression, allowing antigen presentation to CD8+ cells. This interaction improves the hosts ability to identify and destroy infected cells and limits the ability of virus to generate new progeny (Table 1) (11).

Viruses have also been constructed with safety features that prevent undesired infection. A temperature-sensitive mutation in the immediate-early a4 gene leads to inhibition of viral replication at temperatures greater than 39.5°C, thereby offering some protection against a potentially serious viral-mediated illness. Furthermore, an intact thymidine kinase gene confers sensitivity to the antiherpetic drugs acyclovir and gancyclovir. These additional safeguards make attenuated HSV an attractive vector for cancer gene therapy.

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