: PubMed/Jan.16/2008Looks like NC Wong is involved here also:
: J Virol. 2008 Jan 16 [Epub ahead of print] Links
Complement is an Essential Component of the Immune Response to Adeno-Associated Virus Vectors.Zaiss AK, Cotter MJ, White LR, Clark SA, Wong NC, Holers VM, Bartlett JS, Muruve DA.
Department of Biochemistry & Molecular Biology and Department of Medicine, University of Calgary, Alberta, T2N 4N1, Canada; Division of Rheumatology, University of Colorado Health Sciences Center, Denver, CO 80262, USA; Gene Therapy Center, Columbus Children’s Research Institute, Columbus Children’s Hospital, Columbus, OH 43205, USA.
Adeno-associated virus (AAV) vectors are associated with relatively mild host immune responses in vivo. Although AAV induces very weak innate immune responses, neutralizing antibodies against the vector capsid and transgene still occur. To understand further the basis of the antiviral immune response to AAV vectors, studies were performed to characterize AAV interactions with macrophages. Primary mouse macrophages and human THP-1 cells transduced in vitro using an AAV2 vector encoding GFP (AAV2-GFP) did not result in measurable transgene expression. An assessment of internalized vector genomes showed that AAV2 vector uptake was enhanced in the presence of normal but not heat-inactivated or C3-depleted mouse/human serum. Enhanced uptake in the presence of serum coincided with increased macrophage activation as determined by the expression of the NFkappaB-dependent genes such as MIP-2, IL-1beta, IL-8 and MIP-1beta. AAV vector serotypes 1 and 8 also activated human and mouse macrophages in a serum-dependent manner. Immunoprecipitation studies demonstrated the binding of iC3b complement protein to the AAV2 capsid in human serum. AAV2 did not activate the alternative pathway of the complement cascade and lacked cofactor activity for factor I-mediated degradation of C3b to iC3b. Instead, our results suggest that the AAV capsid also binds complement regulatory protein factor H. In vivo, complement receptor 1/2- and C3-deficient mice displayed impaired humoral immunity against AAV2 vectors with a delay in antibody development and significantly lower neutralizing antibody titers. These results show that the complement system is an essential component of the host immune response to AAV.
PMID: 18199646 [PubMed - as supplied by publisher]
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