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Drug
Enzyme
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Target Concepts:
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Query: UMLS:C0001486 (
Adenovirus
)
3,125
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Initiation of
Adenovirus
DNA replication in vitro requires the presence of three viral proteins (pTP, pol,
DBP
) and two cellular transcription factors, NFI and Oct-1, that stimulate replication more than 100-fold. NFI assists in binding and positioning of the DNA polymerase in the origin whereas Oct-1 changes the structure of origin DNA. Optimal templates contain, in addition to origin sequences, the covalently bound viral terminal protein (TP). This terminal protein stimulates the template activity over 20 fold compared to protein-free templates. To study the way in which TP exerts its function in vitro we devised a novel method to isolate and label a short origin containing fragment in which the TP was bound in a functional form. This fragment replicated very efficiently and could be used for studying the binding of other replication proteins. Employing alpha-chymotrypsin digestion we show that for enhancement of replication in vitro only a small part of TP is required.
...
PMID:Adenovirus DNA replication: the function of the covalently bound terminal protein. 129 Dec 41
Adenovirus infection
subverts nucleolar structure and function. B23 is a nucleolar protein present in two isoforms (B23.1 and B23.2) and both isoforms have been identified as stimulatory factors for adenovirus DNA replication. Here, it is demonstrated that the two isoforms of B23, B23.1 and B23.2, interact and co-localize differently with viral DNA replication proteins pTP and
DBP
in adenovirus-infected cells. Thus, the mechanism by which the two proteins stimulate viral DNA replication is likely to differ. These data also demonstrate the importance of testing both isoforms of B23 for interactions with viral proteins and nucleic acids.
...
PMID:Relationship between adenovirus DNA replication proteins and nucleolar proteins B23.1 and B23.2. 1802 92
Adenovirus
(Ad)-based immunization is a popular approach in vaccine development, and Ad-based vectors are renowned for their potential to induce strong CD8
+
T cell responses to the encoded transgene. Surprisingly, we previously found in the mouse Friend retrovirus (FV) model that Ad-based immunization did not induce CD8
+
T cell responses to the FV Leader-Gag-derived immunodominant epitope GagL
85-93
We show now that induction of GagL
85-93
-specific CD8
+
T cells was highly effective when leader-Gag was delivered by plasmid DNA immunization, implying a role for Ad-derived epitopes in mediating unresponsiveness. By immunizing with DNA constructs encoding strings of GagL
85-93
and the two Ad-derived epitopes DNA-binding protein
418-426
(
DBP
418-426
) and hexon
486-494
, we confirmed that Ad epitopes prevent induction of GagL
85-93
-specific CD8
+
T cells. Interestingly, while
DBP
418-426
did not interfere with GagL
85-93
-specific CD8
+
T cell induction, the H-2D
d
-restricted hexon
486-494
suppressed the CD8
+
T cell response to the H-2D
b
-restricted GagL
85-93
strongly in H-2
b/d
mice but not in H-2
b/b
mice. This finding indicates that competition occurs at the level of responding CD8
+
T cells, and we could indeed demonstrate that coimmunization with an interleukin 2 (IL-2)-encoding plasmid restored GagL
85-93
-specific CD8
+
T cell responses to epitope strings in the presence of hexon
486-494
IL-2 codelivery did not restore GagL
85-93
responsiveness in Ad-based immunization, however, likely due to the presence of further epitopes in the Ad vector. Our findings show that seemingly immunodominant transgene epitopes can be dominated by Ad-derived epitopes. These findings underline the importance of thorough characterization of vaccine vectors, and modifications of vectors or immunogens may be required to prevent impaired transgene-specific immune responses.
IMPORTANCE
Ad-based vectors are widely used in experimental preclinical and clinical immunization studies against numerous infectious agents, such as human immunodeficiency virus, Ebola virus,
Plasmodium falciparum
, or
Mycobacterium tuberculosis
Preexisting immunity to Ad-based vectors is widely recognized as a hindrance to the widespread use of Ad-based vectors for immunizations in humans; however, our data show that an immune response to Ad-derived T cell epitopes can also result in loss or impairment of transgene-specific immune responses in prenaive vaccinees due to immune competition. Our results highlight that seemingly immunodominant epitopes may be affected by dominance of vector-derived epitopes, and modifications of the vector design or the immunogens employed in immunization may lead to more effective vaccines.
...
PMID:Immunodominance of Adenovirus-Derived CD8
+
T Cell Epitopes Interferes with the Induction of Transgene-Specific Immunity in Adenovirus-Based Immunization. 2876 77
