Inhibiting AIDS in the central nervous system: gene delivery to protect neurons from HIV.
Gene therapy to treat primary and secondary CNS diseases, including neuro-AIDS, has not yet been effective. New approaches to delivering therapeutic genes to the central nervous system are therefore required. Recombinant SV40 vectors (rSV40) transduce both dividing and quiescent cells efficiently, and so we tested them for their ability to deliver anti-HIV-1 transgenes to terminally differentiated human NT2-derived neurons (NT2-N). These vectors transduced >95% of immature as well as mature human neurons efficiently, without detectable toxicity and without requiring selection. rSV40 gene delivery was stable to retinoic acid-induced neuronal differentiation. The rSV40 vectors used in these studies, SV(RevM10) and SV(AT), respectively carried the cDNAs for RevM10, a trans-dominant mutant of HIV-1 Rev, and human alpha1-antitrypsin. As measured by HIV-1 p24 antigen assays and by immunostaining for gp120, NT2-N treated with these vectors strongly resisted challenge with different strains of HIV-1. Protection from HIV replication and HIV-induced cytotoxicity was conferred by SV(AT) and SV(RevM10) and remained constant throughout retinoic acid-induced neuronal differentiation and for the duration of these studies (> or =11 weeks). rSV40 transduction of human neurons might therefore be a practicable approach to gene delivery for the treatment of CNS diseases, including neuro-AIDS.
Cordelier
Pierre
P
Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Van Bockstaele
Elisabeth
E
Calarota
Sandra A
SA
Strayer
David S
DS
D015526:AIDS Dementia Complex / Q000235:genetics / Q000517:prevention & control*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D015694:Gene Products, rev / Q000235:genetics / Q000378:metabolism; D015757:Genes, rev / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D016655:HIV Core Protein p24 / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000821:virology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013539:Simian virus 40 / Q000235:genetics; D014161:Transduction, Genetic; D019076:Transgenes / Q000235:genetics; D014212:Tretinoin / Q000378:metabolism; D014779:Virus Replication; D054321:rev Gene Products, Human Immunodeficiency Virus
D015694:Gene Products, rev; D016655:HIV Core Protein p24; D054321:rev Gene Products, Human Immunodeficiency Virus; D014212:Tretinoin