Adenovirus binding to the coxsackievirus and adenovirus receptor or integrins is not required to elicit brain inflammation but is necessary to transduce specific neural cell types.
Intracranial administration of adenovirus vectors elicits rapid, capsid-mediated dose-dependent brain inflammation. The mechanisms through which adenovirus capsids trigger inflammation in the brain remain unknown. We determined whether adenovirus interaction with the primary and secondary cell surface receptors for infection (CAR and alphav integrins) was necessary to trigger acute adenovirus-mediated brain inflammation, and, furthermore, whether capsid mutations that abrogated CAR and integrin binding altered vector tropism in the brain. Vectors ablated for CAR binding, but retaining integrin binding function, transduced equivalent areas of brain compared to vectors with wild-type capsids; however, vector tropsim was dramatically altered. Vectors with wild-type capsids predominantly transduced oligodendrocytes, whereas mutation of the fiber protein to ablate CAR binding resulted in a loss of oligodendrocyte transduction and a consequent redirection of transduction to neurons and other types of glial cells. Combined mutations of fiber and penton base that ablate both CAR and integrin binding almost abolished brain transduction. Thus, doubly-ablated capsids engineered to express new ligands should allow complete vector retargeting in the central nervous system. Although transduction by the doubly-ablated vectors was reduced by greater than 95%, inflammation was not reduced compared to wild-type vectors, demonstrating that brain inflammation occurs independently of adenovirus binding and infection of cells via CAR and integrin receptors.
Thomas
Clare E
CE
Molecular Medicine and Gene Therapy Unit, University of Manchester, Manchester, United Kingdom.
Edwards
Penny
P
Wickham
Thomas J
TJ
Castro
Maria G
MG
Lowenstein
Pedro R
PR
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism*; D000257:Adenoviridae Infections / Q000821:virology; D000818:Animals; D002213:Capsid / Q000235:genetics; D036022:Capsid Proteins; D004660:Encephalitis / Q000821:virology; D004770:Enterovirus / Q000378:metabolism*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D007150:Immunohistochemistry; D016023:Integrins / Q000378:metabolism*; D009154:Mutation; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011991:Receptors, Virus / Q000378:metabolism*; D014161:Transduction, Genetic
D036022:Capsid Proteins; D016023:Integrins; D011991:Receptors, Virus; C018315:hexon capsid protein, Adenovirus; C043322:penton protein, adenovirus