Adenovirus persistence

Infants with SCID have profound immunodehciency and present with frequent episodes of diarrhea, pneumonia, otitis, sepsis, and cutaneous infections. Persistent infections with opportunistic organisms such as Pneumocystis carinii, Epstein-Barr virus, Candida albicans, cytomegalovirus, parainhuenzae 3 virus, respiratory syncitial virus, adenovirus, varicella, and bacille Calmette-Guerin (BCG) lead to death within the hrst or second year of life. ADA dehciency also occurs in adults, but with a much later onset and nhlder, but clinically discernible, immunodehciency [3,5]. 

However, a variety of issues have implications for the use of viral vectors in gene therapy. Obvious potential concerns are the immune and inflammatory responses to viral vectors. Patients who received VEGF-121 via an adenoviral vector had increased levels of serum antiadenoviral neutralizing antibodies, but there was no report on an inflammatory response in these patients (27). The use of adenovirus-mediated gene therapy in treating brain tumors has been reported to lead to active brain inflammation as well as persistent (up to three months after treatment) transgene expression (30). 

Dewey RA, Morrissey G, Cowsill CM, et al. Chronic brain inflammation and persistent herpes simplex virus I thymidine kinase expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy implications for clinical trials. Nat Med 1999 5 1256-1263. 

Byrnes AP, MacLaren RE, Charlton HM (1996) Immunological instability of persistent adenovirus vectors in the brain Peripheral exposure to vector leads to renewed inflammation, reduced gene expression, and demyelination. J Neurosci 16 3045-3055. 

Michou AI, Santoro L, Christ M, Julhard V, Pavirani A, Mehtali M (1997) Adenovirus-mediated gene transfer Influence of transgene, mouse strain and type of immune response on persistence of transgene expression. Gene Ther 4 473 82. 

Engelhardt JF, Ye X, Doranz B, Wilson JM. Ablation of E2A in recombinant adenoviruses improves transgene persistence and decreases inflammatory response in mouse liver. Proc Natl Acad Sci USA 1994, 91, 6196-6200. 

Little is known about the in vivo status of human adenovirus during persistence. Because of the strict host range, no suitable and relevant animal model is available to study Ad persistence. In many virus systems it became clear that studies on the molecular interactions of animal viruses with their natural host (e.g., murine cytomegalovirus) provide only limited clues as to the situation of the related human viruses (e.g., human cytomegalovirus) with their host (Hengel et al. 1998). 

Bruder JT, Jie T, McVey DL, Kovesdi I (1997) Expression of gpl9K increases the persistence of transgene expression from an adenovirus vector in the mouse lung and liver. J Virol 71 7623-7628 Bruder JT, Kovesdi I (1997) Adenovirus infection stimulates the Raf/MAPK signaling pathway and induces interleukin-8 expression. J Virol 71 398-404 Burgert H-G (1996) Subversion of the MHC class I antigen presentation pathway by adenoviruses and herpes simplex viruses. Trends Microbiol 4 107-112... 

Kitajewski J, Schneider R, Safer B, Munemitsu S, Samuel C, Thimmappaya B, Shenk T (1986) Adenovirus VAI RNA antagonizes the antiviral action of interferon by preventing activation of the interferon-induced eIF-2 alpha kinase. Cell 45 195-200 Korner H, Burgert H-G (1994) Down-regulation of HLA antigens by the adenovirus type 2 E3/19K protein in a T-lymphoma cell line. J Virol 68 1442-1448 Korner H, Fritzsche U, Burgert H-G (1992) Tumor necrosis factor alpha stimulates expression of adenovirus early region 3 proteins implications for viral persistence. Proc Natl Acad Sci USA 89 11857-11861... 

Lieber A, He C, Meuse L, Himeda C, Wilson C, Kay M (1998) Inhibition of NF-kB activation in combination with bcl-2 expression allows for persistence of first-generation adenovirus vectors in the mouse liver. J Virol 72 9267-9277... 

Zsengeller ZK, Wert SE, Hull WM, Hu X, Yei S, Trapnell BC, Whitsett JA et al. Persistence of replication-deficient adenovirus-mediated gene transfer in lungs of immune-deficient (nu/nu) mice. Hum Gene Ther 1995 6(4) 457-467. 

As a result of these and similar efforts, the persistance of gene expression in vivo has been extended to as long as 12 months [78]. It remains to be determined, however, if these methods can eliminate the immune response against recombinant adenoviruses and their products, whether or not elimination of the immune response results in long-term gene expression, and if these methods will be effective in human gene therapy protocols. 

Nakagawa, 1. et al.. Persistent and secondary adenovirus-mediated hepatic gene expression using adenovirus vector containing CTLA41gG [In Process Citation], Hum. Gene Ther., 9,1739,1998. 

Scaria, A. et al. Adenovirus-mediated persistent cystic fibrosis transmembrane conductance regulator expression in mouse airway epithelium, J. Virol, 72, 7302,1998. 

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