Effect of hypoxia on Ad5 infection, transgene expression and replication.
Gene Ther
; 12(11): 902-10, 2005 Jun.
Article
en En
| MEDLINE
| ID: mdl-15690062
ABSTRACT
Oxygen deprivation (hypoxia) is a common feature of various human maladies, including cardiovascular diseases and cancer; however, the effect of hypoxia on Ad-based gene therapies has not been described. In this study, we evaluated how hypoxia (1% pO(2)) affects different aspects of Ad-based therapies, including attachment and uptake, transgene expression, and replication, in a series of cancer cell lines and primary normal cells. We found that hypoxia had no significant effect on the expression or function of the Ad5 attachment (Coxsackievirus and Adenovirus Receptor) and internalization (alpha(v) integrins) proteins, nor on the human cytomegalovirus-driven expression of an exogenous gene carried by a replication-incompetent Ad. Viral replication, however, was compromised by hypoxic conditions. Our studies revealed hypoxia-induced reductions in E1A levels that were mediated at the post-transcriptional level. E1A drives cells into the viral replication optimal S phase of the cell cycle; consequently, the combination of reduced E1A protein and hypoxia-induced G1 arrest of cells may be responsible for the lack of efficient viral replication under hypoxic conditions. Consequently, while traditional replication-incompetent Ad-based vectors appear to be viable delivery systems for hypoxia-associated disease indications, our studies suggest that Oncolytic Ads may need additional factors to efficiently treat hypoxic regions of human tumors.
Buscar en Google
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Replicación Viral
/
Infecciones por Adenovirus Humanos
/
Adenovirus Humanos
/
Transgenes
Límite:
Humans
Idioma:
En
Revista:
Gene Ther
Asunto de la revista:
GENETICA MEDICA
/
TERAPEUTICA
Año:
2005
Tipo del documento:
Article
País de afiliación:
Estados Unidos