Transfer of a gene encoding the anticandidal protein histatin 3 to salivary glands.
Mucosal candidiasis, the most common opportunistic fungal infection in human immunodeficiency virus (HIV)-infected patients, is an early sign of clinically overt acquired immunodeficiency syndrome (AIDS) and an important cause of morbidity, particularly in HIV-infected children. The appearance of azole-resistant strains of Candida albicans had made clinical management of candidiasis increasingly difficult. We propose a novel approach to the management of candidal infections that involves the use of naturally occurring antifungal proteins, such as the histatins. Histatins are a family of small proteins that are secreted in human saliva. We have constructed recombinant adenovirus vectors that contain the histatin 3 cDNA. These vectors are capable of directing the expression of histatin 3 in the saliva of rats at up to 1,045 micrograms/ml, well above the levels found in normal human saliva. The adenovirus-directed histatin demonstrated a 90% candidacidal effect in the timed-kill assay against both fluconazole-susceptible and fluconazole-resistant strains of C. albicans and inhibited germination by 45% in the same strains. These studies suggest that a gene transfer approach to overexpress naturally occurring antifungal proteins may be useful in the management of mucosal candidiasis.
O'Connell
B C
BC
Clinical Investigations and Patient Care Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, MD 20892, USA.
Xu
T
T
Walsh
T J
TJ
Sein
T
T
Mastrangeli
A
A
Crystal
R G
RG
Oppenheim
F G
FG
Baum
B J
BJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects; D002460:Cell Line; D004274:DNA, Recombinant; D004847:Epithelial Cells; D015725:Fluconazole / Q000494:pharmacology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D054808:Histatins; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D011506:Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D012463:Saliva / Q000737:chemistry; D012469:Salivary Glands / Q000737:chemistry; D012471:Salivary Proteins and Peptides / Q000235:genetics* / Q000378:metabolism; D013363:Submandibular Gland / Q000737:chemistry
D000935:Antifungal Agents; D004274:DNA, Recombinant; C068075:HTN3 protein, human; D054808:Histatins; D011506:Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012471:Salivary Proteins and Peptides; D015725:Fluconazole