Long-term protection against human papillomavirus E7-positive tumor by a single vaccination of adeno-associated virus vectors encoding a fusion protein of inactivated E7 of human papillomavirus 16/18 and heat shock protein 70
Journal
Human Gene Therapy
Journal Volume
21
Journal Issue
1
Pages
109-119
Date Issued
2010
Author(s)
Abstract
We investigated a gene vaccine strategy against human papillomavirus (HPV)-induced cancer and premalignant diseases, using adeno-associated virus (AAV) vector encoding the viral E7 oncoproteins as the tumor antigens from HPV serotypes 16 (HPV16) and 18 (HPV18). Genetically inactivated E7 proteins were fused with a heat shock protein 70 (hsp70) to minimize the risk of cell transformation and enhance immune responses. The fusion protein gene was packaged in AAV serotype 1 or 2 (AAV1 or 2) for efficient in vivo gene expression. Our results showed that after a single intramuscular injection, the AAV1 vector elicited stronger HPV-specific cytotoxic T lymphocyte (CTL) responses and interferon-γ secretion when compared with the AAV2 vector. Prophylactic immunization with AAV1 protected 100% of the mice from tumor growth for more than 1 year, whereas all the control mice immunized with either a LacZ vector or saline grew large tumors and died within 6 weeks after inoculation of E7-positive tumor cell line TC-1. In addition, this single-dose AAV1 vaccination completely protected the mice against second and third challenges with higher numbers of TC-1 cells. Despite lower CTL responses against the E7 antigens, AAV2 vector prophylactic immunization was also sufficient to protect 100% of the mice against the initial and second tumor challenges and 70% of the mice against the third challenge. In addition, therapeutic immunization with AAV1 after palpable tumor formation inhibited tumor growth and caused tumor regression in some mice. Thus, our studies support the potential of AAV vectors as a genetic vaccine for the prevention and treatment of HPV-induced malignancies. ? 2010 Mary Ann Liebert, Inc.
SDGs
Other Subjects
aav1 1618e7hsp70; aav2 1618e7hsp70; beta galactosidase; cancer vaccine; gamma interferon; heat shock protein 70; hybrid protein; parvovirus vector; protein E7; unclassified drug; animal experiment; animal model; antineoplastic activity; article; cancer immunization; cancer inhibition; cell transformation; controlled study; cytokine release; cytotoxic T lymphocyte; drug efficacy; female; gene expression; human; human cell; Human papillomavirus type 16; Human papillomavirus type 18; immune response; mouse; neoplasm; nonhuman; serotype; tumor cell line; tumor volume; Animals; Antigens, Neoplasm; Cancer Vaccines; Cell Line; Dependovirus; Epitopes; Female; Genetic Vectors; HSP70 Heat-Shock Proteins; Human papillomavirus 16; Human papillomavirus 18; Humans; Mice; Neoplasms; Papillomavirus E7 Proteins; Recombinant Fusion Proteins; T-Lymphocytes, Cytotoxic; Time Factors; Treatment Outcome; Vaccination; Adeno-associated virus; Human papillomavirus; Mus
Type
journal article