Adenoviral vectors can impair adrenocortical steroidogenesis: clinical implications for natural infections and gene therapy.
Recombinant adenoviral vectors are effective in transferring foreign genes to a variety of cells and tissue types, both in vitro and in vivo. However, during the gene transfer, they may alter the principal function and local environment of transfected cells. Increasing evidence exists for a selective adrenotropism of adenovirus during infections and gene transfer. Therefore, using bovine adrenocortical cells in primary culture, we analyzed the influence of different adenoviral deletion mutants on cell morphology and physiology. Transfection of cells with an E1/E3-deleted adenoviral vector, engineered to express a modified form of the Aequorea victoria green fluorescent protein, was highly efficient, as documented by fluorescent microscopy. Ultrastructural analysis, however, demonstrated nuclear fragmentation and mitochondrial alterations in addition to intranuclear viral particles. Basal secretion of 17-OH-progesterone, 11-deoxycortisol, and cortisol was significantly increased by E1/E3-deleted vectors; yet, the corticotropin-stimulated release of these steroids was decreased. Interestingly, neither purified viral capsids nor E3/E4-deleted adenoviral mutants altered basal and stimulated steroidogenesis of adrenocortical cells. An intact adrenal response is crucial for adaptation to stress and survival. Therefore, the implications of our findings need to be considered in patients with adenoviral infections and those undergoing clinical studies using adenoviral gene transfer. At the same time, the high level of transfection in adrenocortical cells might make appropriately modified adenoviral vectors suitable for gene therapy of adrenocortical carcinomas with poor prognosis.
Alesci
Salvatore
S
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1583, USA. alescis@mail.nih.gov
Ramsey
Walter J
WJ
Bornstein
Stefan R
SR
Chrousos
George P
GP
Hornsby
Peter J
PJ
Benvenga
Salvatore
S
Trimarchi
Francesco
F
Ehrhart-Bornstein
Monika
M
D000256:Adenoviridae / Q000235:genetics*; D000302:Adrenal Cortex / Q000166:cytology / Q000502:physiology*; D000305:Adrenal Cortex Hormones / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D002213:Capsid; D002417:Cattle; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D006854:Hydrocortisone / Q000378:metabolism*; D007239:Infections / Q000235:genetics*; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D008854:Microscopy, Electron; D011994:Recombinant Proteins / Q000032:analysis; D015398:Signal Transduction; D013936:Thymidine / Q000378:metabolism
D000305:Adrenal Cortex Hormones; D008164:Luminescent Proteins; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; D000324:Adrenocorticotropic Hormone; D004247:DNA; D013936:Thymidine; D006854:Hydrocortisone