Herpes Simplex Virus 1 (HSV-1)-Based Vectors - Viral Vector Approaches in Neurobiology and Brain Diseases - page 64

virus life cycle, one of which is to block the arrest in translation that
usually occurs in virus-infected cells as an antiviral response that
prevents virus replication. This effect is mediated through the cel-
lular RNA-dependent protein kinase (PKR), which phosphorylates
the translation initiation factor eIF2a, thereby stopping translation
[ 87 ]. ICP34.5 recruits protein phosphatase 1a (PP1a) to rephos-
phorylate eIF2a, allowing protein translation and continued virus
replication. Tumor cells often display an impaired PKR pathway
and/or elevated levels of eIF2a, allowing replication of ICP34.5-
deleted viruses since the inactivation of the PKR response is less
critical in this context. Secondly, it has been recently demonstrated
that ICP34.5 is involved in the inhibition of autophagy, another
defense mechanism of infected cells, through the inhibition of
Beclin 1, a critical factor involved in this pathway [ 88 , 89 ].
So far, several oncolytic HSV-1 strains have been developed
with particularly efforts for the treatment of malignant glioma
[ 16 ]. Malignant gliomas are the most common primary malignant
brain tumors and are almost universally fatal despite aggressive
therapies such as surgery, radiotherapy, and chemotherapy. Recent
trials using genetically engineered HSV-1 strains deleted for one or
both copies of ICP34.5, alone or together with other deletions
[ 90 - 92 ], have been quite encouraging, showing these viruses to
be nontoxic for normal cells but remaining lytic in tumor cells.
In early clinical trials, however, treatment with the fi rst generations
of oncolytic viruses did not signifi cantly affect tumor growth. This
suboptimal result may be explained by the fact that deletion of the
γ 34.5 gene signifi cantly reduced viral growth also in rapidly dividing

cells. Pending results of current phase trials will be an important
step in fulfi lling the potential of oncolytic vectors in the treatment
of patients with newly diagnosed malignant glioma.
In the meantime, a variety of strategies have been pursued and
many others are still evolving, based on the results obtained in
clinical trials, to enhance the potency of oncolytic viruses. Towards
this end, oncolytic HSV-1 vectors have been further modifi ed,
either to abrogate viral-induced MHC class I downregulation
through the deletion of the US12 gene, which encodes the ICP47
protein [ 15 , 93 ], or to enhance their antitumor effi cacy, through
the incorporation of expression cassettes to deliver tumor toxic
transgenes. The impact of these clinical studies on the design of
more effi cient oncolytic HSV vectors needs to be carefully consid-
ered. A number of cytokines have been tested using various onco-
lytic HSV-1 strains [ 94 , 95 ] as carriers. A virus that expresses
IL-12, a cytokine that is known to produce antitumor immune
responses as well as antiangiogenic effects (without causing a
decrease in virus replication in in vivo preclinical studies), is being
advanced for potential clinical use pending the results of the prior
studies. The viral approach to deliver the cytokine locally also