Primary adenovirus-specific cytotoxic T lymphocyte response occurs after viral clearance and liver enzyme elevation.
The virus-specific cytotoxic T lymphocyte (CTL) response is a major obstacle to effective delivery of adenovirus gene therapy. However, its relative role in viral clearance, transgene elimination and hepatotoxicity remains unclear. In this paper, we present an analysis of viral clearance and liver toxicity in relation to the induction of the virus-specific CD8 T-cell response revealed by an MHC class I tetramer. A surprisingly high number of tetramer+ CD8 T cells were found in the liver and lung and reached peak values at days 8 and 10, respectively, post-infection. Nearly 100% of these tetramer+ CD8 T cells expressed high levels of granzyme B and IFNgamma. Remarkably, liver viral load and liver enzyme elevation peaked early, at days 2 and 4, respectively, post-infection, before the specific CTL response was detectable. After generation of CTLs, there was only minimal liver damage or further decrease in virus titer. These results indicated that the primary peak response of tetramer+ CTLs does not correlate with the elimination of adenovirus or liver cytotoxic response.
Chen
J
J
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-0007, USA.
Zajac
A J
AJ
McPherson
S A
SA
Hsu
H-C
HC
Yang
P
P
Wu
Q
Q
Xu
X
X
Wang
X
X
Fujihashi
K
K
Curiel
D T
DT
Mountz
J D
JD
D000256:Adenoviridae; D000257:Adenoviridae Infections / Q000276:immunology*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D053804:Granzymes; D015395:Histocompatibility Antigens Class I / Q000008:administration & dosage; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000032:analysis; D008099:Liver / Q000201:enzymology / Q000821:virology*; D008168:Lung / Q000821:virology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000032:analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013997:Time Factors
D015395:Histocompatibility Antigens Class I; D007371:Interferon-gamma; D000410:Alanine Transaminase; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases