Adenoviral vectors can impair adrenocortical steroidogenesis: Clinical implications for natural infections and gene therapy

Abstract

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 E1͞E3-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 E1͞E3-deleted vectors; yet, the corticotropinstimulated release of these steroids was decreased. Interestingly, neither purified viral capsids nor E3͞E4-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.

Differentiation and Regeneration of Adrenal Tissues: An Initial Step toward Regeneration Therapy for Steroid Insufficiency

“…Adenoviruses are easily incorporated into the liver, but they also show comparatively good uptake into the adrenal glands [49]. A detailed investigation into the effects of various adenovirus variants regarding the introduction efficiency and responsiveness to ACTH of bovine adrenocortical cells has been reported [50]. This report states that although the E1/E3-deficient type of adenovirus was optimal for the introduction efficiency into bovine adrenocortical cells, it lowered their responsiveness to ACTH.…”

Genetics of Congenital Adrenal Hyperplasia

“…109,110 These approaches restore the impaired adrenocortical function in 21-hydroxylase knockout mice and bovine adrenocortical cells. [110][111][112] Gene or stem-cell transplantation therapies could be a feasible option for treatment of CAH in the future.…”

Adenovirus vectors differentially modulate proliferation of pituitary lactotrophs in primary culture in a mitogen and infection time-dependent manner

“…However, infection at a MOI of 20 increased basal secretion and conversely decreased secretagogue-stimulated secretion of adrenocorticotropin (ACTH) and luteinizing hormone. Adenoviruses expressing green fluorescent protein and bgal also increased the basal secretion of adrenocortical steroids such as cortisol, 17-hydroxyprogesterone, and 11-deoxycortisol and decreased their ACTH-stimulated secretion in bovine adrenocortical cells in the primary culture (Alesci et al 2002). In association with the increase in basal hormone secretion, an increase in [ 3 H]thymidine uptake is observed in adenovirusinfected cells, suggesting that the increased basal secretion by adenoviruses is caused by an increased cell number.…”

“…This study demonstrates that infection of lactotrophs with adenovirus vectors expressing bgal markedly increases basal proliferation of lactotrophs. Since a similar increase in basal proliferation by adenovirus vectors is also observed in adrenocortical cells in the primary culture (Alesci et al 2002), it is likely that adenovirus vectors generally stimulate basal proliferation in endocrine cells in the primary culture. In contrast to the stimulation of basal proliferation, the adenovirus vectors differentially inhibited mitogen-induced proliferation in a mitogen-dependent manner.…”