Attenuated reovirus
Compositions and methods are provided that relate to an attenuated reovirus exhibiting oncolytic activity toward cancer cells while displaying reduced lytic activity toward non-malignant cells. Exemplified is an attenuated human reovirus derived from persistently infected fibrosarcoma cells that lacks wild-type reovirus S1 and S4 genes and consequently lacks a detectable reoviral outer capsid σ1 protein and expresses a mutated reoviral outer capsid σ3 protein.
1. An attenuated reovirus, comprising a reovirus genome that comprises a modification in the wild-type S1 gene, wherein the modification is selected from
(a) a deletion of a nucleotide at nucleotide sequence position 26 of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:9 or SEQ ID NO:10;
(b) a mutation at nucleotide sequence position 359 of SEQ ID NO: 9 or SEQ ID NO:10;
(c) a mutation at nucleotide sequence position 392 of SEQ ID NO: 9 or SEQ ID NO:10;
(d) a mutation at nucleotide sequence position 763 of SEQ ID NO: 9 or SEQ ID NO:10; and
(e) a mutation at nucleotide sequence position 912 of SEQ ID NO: 9 or SEQ ID NO:10, wherein the mutation at nucleotide sequence position 912 causes a substitution of isoleucine to methionine in the corresponding amino acid sequence.
2. The attenuated reovirus of claim 1 , wherein the modification is the deletion of a nucleotide at nucleotide sequence position 26 of SEQ ID NO: 9 or SEQ ID NO:10.
3. The attenuated reovirus of claim 1 , wherein the modification is the mutation at nucleotide sequence position 359 of SEQ ID NO: 9 or SEQ ID NO:10.
4. The attenuated reovirus of claim 3 , wherein the mutation at nucleotide sequence position 359 causes a substitution of lysine to proline in the corresponding amino acid sequence.
5. The attenuated reovirus of claim 1 , wherein the modification is the mutation at nucleotide sequence position 392 of SEQ ID NO:9 or SEQ ID NO:10.
6. The attenuated reovirus of claim 5 , wherein the mutation at nucleotide sequence position 392 causes a substitution of valine to alanine in the corresponding amino acid sequence.
7. The attenuated reovirus of claim 1 , wherein the modification is the mutation at nucleotide sequence position 763 of SEQ ID NO: 9 or SEQ ID NO:10.
8. The attenuated reovirus of claim 7 , wherein the mutation at nucleotide sequence position 763 causes a substitution of glutamine to a stop codon in the corresponding amino acid sequence.