RapamycinFungusV1, Main, Exploration, bibRecord, 000568

Kaposi's Sarcoma-Associated Herpesvirus Latency Locus Renders B Cells Hyperresponsive to Secondary Infections.

Identifieur interne : 000568 ( Main/Exploration ); précédent : 000567; suivant : 000569

Kaposi's Sarcoma-Associated Herpesvirus Latency Locus Renders B Cells Hyperresponsive to Secondary Infections.

Auteurs : Sang-Hoon Sin [États-Unis] ; Anthony B. Eason [États-Unis] ; Rachele Bigi [États-Unis] ; Yongbaek Kim [Corée du Sud] ; Sunah Kang [États-Unis] ; Kelly Tan [États-Unis] ; Tischan A. Seltzer [États-Unis] ; Raman Venkataramanan [États-Unis] ; Hyowon An [États-Unis] ; Dirk P. Dittmer [États-Unis]

Source :

Journal of virology [ 1098-5514 ] ; 2018.

RBID : pubmed:30021906

Descripteurs français

English descriptors

KwdEn :
- Animals (MeSH), Antineoplastic Agents (pharmacology), B-Lymphocytes (drug effects), B-Lymphocytes (immunology), B-Lymphocytes (virology), Cell Differentiation (drug effects), Coinfection (MeSH), Disease Resistance (genetics), Everolimus (pharmacology), Herpesvirus 8, Human (drug effects), Herpesvirus 8, Human (genetics), Herpesvirus 8, Human (immunology), Humans (MeSH), Hypergammaglobulinemia (genetics), Hypergammaglobulinemia (immunology), Hypergammaglobulinemia (virology), Immunosuppressive Agents (pharmacology), Mice, Inbred BALB C (MeSH), Mice, Knockout (MeSH), Mice, Nude (MeSH), MicroRNAs (genetics), MicroRNAs (immunology), Plasmacytoma (genetics), Plasmacytoma (immunology), Plasmacytoma (virology), RNA, Viral (genetics), RNA, Viral (immunology), Receptors, IgG (deficiency), Receptors, IgG (genetics), Receptors, IgG (immunology), Sarcoma, Kaposi (genetics), Sarcoma, Kaposi (immunology), Sarcoma, Kaposi (virology), Terpenes (pharmacology), Virus Latency (MeSH), Zika Virus (drug effects), Zika Virus (genetics), Zika Virus (immunology), Zika Virus Infection (genetics), Zika Virus Infection (immunology), Zika Virus Infection (virology).
MESH :
- chemical , deficiency : Receptors, IgG.
- chemical , genetics : MicroRNAs, RNA, Viral, Receptors, IgG.
- chemical , immunology : MicroRNAs, RNA, Viral, Receptors, IgG.
- chemical , pharmacology : Antineoplastic Agents, Everolimus, Immunosuppressive Agents, Terpenes.
- drug effects : B-Lymphocytes, Cell Differentiation, Herpesvirus 8, Human, Zika Virus.
- genetics : Disease Resistance, Herpesvirus 8, Human, Hypergammaglobulinemia, Plasmacytoma, Sarcoma, Kaposi, Zika Virus, Zika Virus Infection.
- immunology : B-Lymphocytes, Herpesvirus 8, Human, Hypergammaglobulinemia, Plasmacytoma, Sarcoma, Kaposi, Zika Virus, Zika Virus Infection.
- virology : B-Lymphocytes, Hypergammaglobulinemia, Plasmacytoma, Sarcoma, Kaposi, Zika Virus Infection.
- Animals, Coinfection, Humans, Mice, Inbred BALB C, Mice, Knockout, Mice, Nude, Virus Latency.

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) induces B cell hyperplasia and neoplasia, such as multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL). To explore KSHV-induced B cell reprogramming in vivo, we expressed the KSHV latency locus, inclusive of all viral microRNAs (miRNAs), in B cells of transgenic mice in the absence of the inhibitory FcγRIIB receptor. The BALB/c strain was chosen as this is the preferred model to study B cell differentiation. The mice developed hyperglobulinemia, plasmacytosis, and B lymphoid hyperplasia. This phenotype was ameliorated by everolimus, which is a rapamycin derivative used for the treatment of mantle cell lymphoma. KSHV latency mice exhibited hyperresponsiveness to the T-dependent (TD) antigen mimic anti-CD40 and increased incidence of pristane-induced inflammation. Lastly, the adaptive immunity against a secondary infection with Zika virus (ZIKV) was markedly enhanced. These phenotypes are consistent with KSHV lowering the activation threshold of latently infected B cells, which may be beneficial in areas of endemicity, where KSHV is acquired in childhood and infections are common.IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) establishes latency in B cells and is stringently linked to primary effusion lymphoma (PEL) and the premalignant B cell hyperplasia multicentric Castleman's disease (MCD). To investigate potential genetic background effects, we expressed the KSHV miRNAs in BALB/c transgenic mice. BALB/c mice are the preferred strain for B cell hybridoma development because of their propensity to develop predictable B cell responses to antigen. The BALB/c latency mice exhibited a higher incidence of B cell hyperplasia as well as sustained hyperglobulinemia. The development of neutralizing antibodies against ZIKV was augmented in BALB/c latency mice. Hyperglobulinemia was dampened by everolimus, a derivative of rapamycin, suggesting a role for mTOR inhibitors in managing immune activation, which is hallmark of KSHV infection as well as HIV infection.

DOI: 10.1128/JVI.01138-18
PubMed: 30021906
PubMed Central: PMC6146794

Affiliations:

Links toward previous steps (curation, corpus...)

to stream Main, to step Corpus: 000497
to stream Main, to step Curation: 000497

Le document en format XML

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<author><name sortKey="Sin, Sang Hoon" sort="Sin, Sang Hoon" uniqKey="Sin S" first="Sang-Hoon" last="Sin">Sang-Hoon Sin</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Microbiology and Immunology, Programs in Global Oncology and Virology, Lineberger Comprehensive Cancer Center and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA sang-hoon_sin@med.unc.edu.</nlm:affiliation>
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<author><name sortKey="An, Hyowon" sort="An, Hyowon" uniqKey="An H" first="Hyowon" last="An">Hyowon An</name>
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<placeName><region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
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<country xml:lang="fr">États-Unis</country>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Kaposi's Sarcoma-Associated Herpesvirus Latency Locus Renders B Cells Hyperresponsive to Secondary Infections.</title>
<author><name sortKey="Sin, Sang Hoon" sort="Sin, Sang Hoon" uniqKey="Sin S" first="Sang-Hoon" last="Sin">Sang-Hoon Sin</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Microbiology and Immunology, Programs in Global Oncology and Virology, Lineberger Comprehensive Cancer Center and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA sang-hoon_sin@med.unc.edu.</nlm:affiliation>
<country wicri:rule="url">États-Unis</country>
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<placeName><region type="state">Caroline du Nord</region>
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</placeName>
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<author><name sortKey="Eason, Anthony B" sort="Eason, Anthony B" uniqKey="Eason A" first="Anthony B" last="Eason">Anthony B. Eason</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, Programs in Global Oncology and Virology, Lineberger Comprehensive Cancer Center and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea>
<placeName><region type="state">Caroline du Nord</region>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, Programs in Global Oncology and Virology, Lineberger Comprehensive Cancer Center and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea>
<placeName><region type="state">Caroline du Nord</region>
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</placeName>
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<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Laboratory of Veterinary Clinical Pathology, College of Veterinary Medicine, Seoul National University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
<orgName type="university">Université nationale de Séoul</orgName>
</affiliation>
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<author><name sortKey="Kang, Sunah" sort="Kang, Sunah" uniqKey="Kang S" first="Sunah" last="Kang">Sunah Kang</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Microbiology and Immunology, Programs in Global Oncology and Virology, Lineberger Comprehensive Cancer Center and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, Programs in Global Oncology and Virology, Lineberger Comprehensive Cancer Center and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea>
<placeName><region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
</affiliation>
</author>
<author><name sortKey="Tan, Kelly" sort="Tan, Kelly" uniqKey="Tan K" first="Kelly" last="Tan">Kelly Tan</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Microbiology and Immunology, Programs in Global Oncology and Virology, Lineberger Comprehensive Cancer Center and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, Programs in Global Oncology and Virology, Lineberger Comprehensive Cancer Center and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea>
<placeName><region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
</affiliation>
</author>
<author><name sortKey="Seltzer, Tischan A" sort="Seltzer, Tischan A" uniqKey="Seltzer T" first="Tischan A" last="Seltzer">Tischan A. Seltzer</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Microbiology and Immunology, Programs in Global Oncology and Virology, Lineberger Comprehensive Cancer Center and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, Programs in Global Oncology and Virology, Lineberger Comprehensive Cancer Center and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea>
<placeName><region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
</affiliation>
</author>
<author><name sortKey="Venkataramanan, Raman" sort="Venkataramanan, Raman" uniqKey="Venkataramanan R" first="Raman" last="Venkataramanan">Raman Venkataramanan</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
<wicri:cityArea>Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="An, Hyowon" sort="An, Hyowon" uniqKey="An H" first="Hyowon" last="An">Hyowon An</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Statistics & Operations Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Statistics & Operations Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea>
<placeName><region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
</affiliation>
</author>
<author><name sortKey="Dittmer, Dirk P" sort="Dittmer, Dirk P" uniqKey="Dittmer D" first="Dirk P" last="Dittmer">Dirk P. Dittmer</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Microbiology and Immunology, Programs in Global Oncology and Virology, Lineberger Comprehensive Cancer Center and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, Programs in Global Oncology and Virology, Lineberger Comprehensive Cancer Center and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea>
<placeName><region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
</affiliation>
</author>
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<series><title level="j">Journal of virology</title>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term>
<term>Antineoplastic Agents (pharmacology)</term>
<term>B-Lymphocytes (drug effects)</term>
<term>B-Lymphocytes (immunology)</term>
<term>B-Lymphocytes (virology)</term>
<term>Cell Differentiation (drug effects)</term>
<term>Coinfection (MeSH)</term>
<term>Disease Resistance (genetics)</term>
<term>Everolimus (pharmacology)</term>
<term>Herpesvirus 8, Human (drug effects)</term>
<term>Herpesvirus 8, Human (genetics)</term>
<term>Herpesvirus 8, Human (immunology)</term>
<term>Humans (MeSH)</term>
<term>Hypergammaglobulinemia (genetics)</term>
<term>Hypergammaglobulinemia (immunology)</term>
<term>Hypergammaglobulinemia (virology)</term>
<term>Immunosuppressive Agents (pharmacology)</term>
<term>Mice, Inbred BALB C (MeSH)</term>
<term>Mice, Knockout (MeSH)</term>
<term>Mice, Nude (MeSH)</term>
<term>MicroRNAs (genetics)</term>
<term>MicroRNAs (immunology)</term>
<term>Plasmacytoma (genetics)</term>
<term>Plasmacytoma (immunology)</term>
<term>Plasmacytoma (virology)</term>
<term>RNA, Viral (genetics)</term>
<term>RNA, Viral (immunology)</term>
<term>Receptors, IgG (deficiency)</term>
<term>Receptors, IgG (genetics)</term>
<term>Receptors, IgG (immunology)</term>
<term>Sarcoma, Kaposi (genetics)</term>
<term>Sarcoma, Kaposi (immunology)</term>
<term>Sarcoma, Kaposi (virology)</term>
<term>Terpenes (pharmacology)</term>
<term>Virus Latency (MeSH)</term>
<term>Zika Virus (drug effects)</term>
<term>Zika Virus (genetics)</term>
<term>Zika Virus (immunology)</term>
<term>Zika Virus Infection (genetics)</term>
<term>Zika Virus Infection (immunology)</term>
<term>Zika Virus Infection (virology)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>ARN viral (génétique)</term>
<term>ARN viral (immunologie)</term>
<term>Animaux (MeSH)</term>
<term>Antinéoplasiques (pharmacologie)</term>
<term>Co-infection (MeSH)</term>
<term>Différenciation cellulaire (effets des médicaments et des substances chimiques)</term>
<term>Herpèsvirus humain de type 8 (effets des médicaments et des substances chimiques)</term>
<term>Herpèsvirus humain de type 8 (génétique)</term>
<term>Herpèsvirus humain de type 8 (immunologie)</term>
<term>Humains (MeSH)</term>
<term>Hypergammaglobulinémie (génétique)</term>
<term>Hypergammaglobulinémie (immunologie)</term>
<term>Hypergammaglobulinémie (virologie)</term>
<term>Immunosuppresseurs (pharmacologie)</term>
<term>Infection par le virus Zika (génétique)</term>
<term>Infection par le virus Zika (immunologie)</term>
<term>Infection par le virus Zika (virologie)</term>
<term>Latence virale (MeSH)</term>
<term>Lymphocytes B (effets des médicaments et des substances chimiques)</term>
<term>Lymphocytes B (immunologie)</term>
<term>Lymphocytes B (virologie)</term>
<term>Plasmocytome (génétique)</term>
<term>Plasmocytome (immunologie)</term>
<term>Plasmocytome (virologie)</term>
<term>Récepteurs du fragment Fc des IgG (déficit)</term>
<term>Récepteurs du fragment Fc des IgG (génétique)</term>
<term>Récepteurs du fragment Fc des IgG (immunologie)</term>
<term>Résistance à la maladie (génétique)</term>
<term>Sarcome de Kaposi (génétique)</term>
<term>Sarcome de Kaposi (immunologie)</term>
<term>Sarcome de Kaposi (virologie)</term>
<term>Souris de lignée BALB C (MeSH)</term>
<term>Souris knockout (MeSH)</term>
<term>Souris nude (MeSH)</term>
<term>Terpènes (pharmacologie)</term>
<term>Virus Zika (effets des médicaments et des substances chimiques)</term>
<term>Virus Zika (génétique)</term>
<term>Virus Zika (immunologie)</term>
<term>microARN (génétique)</term>
<term>microARN (immunologie)</term>
<term>Évérolimus (pharmacologie)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="deficiency" xml:lang="en"><term>Receptors, IgG</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>MicroRNAs</term>
<term>RNA, Viral</term>
<term>Receptors, IgG</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>MicroRNAs</term>
<term>RNA, Viral</term>
<term>Receptors, IgG</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antineoplastic Agents</term>
<term>Everolimus</term>
<term>Immunosuppressive Agents</term>
<term>Terpenes</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>B-Lymphocytes</term>
<term>Cell Differentiation</term>
<term>Herpesvirus 8, Human</term>
<term>Zika Virus</term>
</keywords>
<keywords scheme="MESH" qualifier="déficit" xml:lang="fr"><term>Récepteurs du fragment Fc des IgG</term>
</keywords>
<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Différenciation cellulaire</term>
<term>Herpèsvirus humain de type 8</term>
<term>Lymphocytes B</term>
<term>Virus Zika</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Disease Resistance</term>
<term>Herpesvirus 8, Human</term>
<term>Hypergammaglobulinemia</term>
<term>Plasmacytoma</term>
<term>Sarcoma, Kaposi</term>
<term>Zika Virus</term>
<term>Zika Virus Infection</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>ARN viral</term>
<term>Herpèsvirus humain de type 8</term>
<term>Hypergammaglobulinémie</term>
<term>Infection par le virus Zika</term>
<term>Plasmocytome</term>
<term>Récepteurs du fragment Fc des IgG</term>
<term>Résistance à la maladie</term>
<term>Sarcome de Kaposi</term>
<term>Virus Zika</term>
<term>microARN</term>
</keywords>
<keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>ARN viral</term>
<term>Herpèsvirus humain de type 8</term>
<term>Hypergammaglobulinémie</term>
<term>Infection par le virus Zika</term>
<term>Lymphocytes B</term>
<term>Plasmocytome</term>
<term>Récepteurs du fragment Fc des IgG</term>
<term>Sarcome de Kaposi</term>
<term>Virus Zika</term>
<term>microARN</term>
</keywords>
<keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>B-Lymphocytes</term>
<term>Herpesvirus 8, Human</term>
<term>Hypergammaglobulinemia</term>
<term>Plasmacytoma</term>
<term>Sarcoma, Kaposi</term>
<term>Zika Virus</term>
<term>Zika Virus Infection</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antinéoplasiques</term>
<term>Immunosuppresseurs</term>
<term>Terpènes</term>
<term>Évérolimus</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Hypergammaglobulinémie</term>
<term>Infection par le virus Zika</term>
<term>Lymphocytes B</term>
<term>Plasmocytome</term>
<term>Sarcome de Kaposi</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>B-Lymphocytes</term>
<term>Hypergammaglobulinemia</term>
<term>Plasmacytoma</term>
<term>Sarcoma, Kaposi</term>
<term>Zika Virus Infection</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Coinfection</term>
<term>Humans</term>
<term>Mice, Inbred BALB C</term>
<term>Mice, Knockout</term>
<term>Mice, Nude</term>
<term>Virus Latency</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Co-infection</term>
<term>Humains</term>
<term>Latence virale</term>
<term>Souris de lignée BALB C</term>
<term>Souris knockout</term>
<term>Souris nude</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">Kaposi's sarcoma-associated herpesvirus (KSHV) induces B cell hyperplasia and neoplasia, such as multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL). To explore KSHV-induced B cell reprogramming <i>in vivo</i>
, we expressed the KSHV latency locus, inclusive of all viral microRNAs (miRNAs), in B cells of transgenic mice in the absence of the inhibitory FcγRIIB receptor. The BALB/c strain was chosen as this is the preferred model to study B cell differentiation. The mice developed hyperglobulinemia, plasmacytosis, and B lymphoid hyperplasia. This phenotype was ameliorated by everolimus, which is a rapamycin derivative used for the treatment of mantle cell lymphoma. KSHV latency mice exhibited hyperresponsiveness to the T-dependent (TD) antigen mimic anti-CD40 and increased incidence of pristane-induced inflammation. Lastly, the adaptive immunity against a secondary infection with Zika virus (ZIKV) was markedly enhanced. These phenotypes are consistent with KSHV lowering the activation threshold of latently infected B cells, which may be beneficial in areas of endemicity, where KSHV is acquired in childhood and infections are common.<b>IMPORTANCE</b>
 Kaposi's sarcoma-associated herpesvirus (KSHV) establishes latency in B cells and is stringently linked to primary effusion lymphoma (PEL) and the premalignant B cell hyperplasia multicentric Castleman's disease (MCD). To investigate potential genetic background effects, we expressed the KSHV miRNAs in BALB/c transgenic mice. BALB/c mice are the preferred strain for B cell hybridoma development because of their propensity to develop predictable B cell responses to antigen. The BALB/c latency mice exhibited a higher incidence of B cell hyperplasia as well as sustained hyperglobulinemia. The development of neutralizing antibodies against ZIKV was augmented in BALB/c latency mice. Hyperglobulinemia was dampened by everolimus, a derivative of rapamycin, suggesting a role for mTOR inhibitors in managing immune activation, which is hallmark of KSHV infection as well as HIV infection.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">30021906</PMID>
<DateCompleted><Year>2018</Year>
<Month>09</Month>
<Day>18</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>04</Month>
<Day>07</Day>
</DateRevised>
<Article PubModel="Electronic-Print"><Journal><ISSN IssnType="Electronic">1098-5514</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>92</Volume>
<Issue>19</Issue>
<PubDate><Year>2018</Year>
<Month>10</Month>
<Day>01</Day>
</PubDate>
</JournalIssue>
<Title>Journal of virology</Title>
<ISOAbbreviation>J Virol</ISOAbbreviation>
</Journal>
<ArticleTitle>Kaposi's Sarcoma-Associated Herpesvirus Latency Locus Renders B Cells Hyperresponsive to Secondary Infections.</ArticleTitle>
<ELocationID EIdType="pii" ValidYN="Y">e01138-18</ELocationID>
<ELocationID EIdType="doi" ValidYN="Y">10.1128/JVI.01138-18</ELocationID>
<Abstract><AbstractText>Kaposi's sarcoma-associated herpesvirus (KSHV) induces B cell hyperplasia and neoplasia, such as multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL). To explore KSHV-induced B cell reprogramming <i>in vivo</i>
, we expressed the KSHV latency locus, inclusive of all viral microRNAs (miRNAs), in B cells of transgenic mice in the absence of the inhibitory FcγRIIB receptor. The BALB/c strain was chosen as this is the preferred model to study B cell differentiation. The mice developed hyperglobulinemia, plasmacytosis, and B lymphoid hyperplasia. This phenotype was ameliorated by everolimus, which is a rapamycin derivative used for the treatment of mantle cell lymphoma. KSHV latency mice exhibited hyperresponsiveness to the T-dependent (TD) antigen mimic anti-CD40 and increased incidence of pristane-induced inflammation. Lastly, the adaptive immunity against a secondary infection with Zika virus (ZIKV) was markedly enhanced. These phenotypes are consistent with KSHV lowering the activation threshold of latently infected B cells, which may be beneficial in areas of endemicity, where KSHV is acquired in childhood and infections are common.<b>IMPORTANCE</b>
 Kaposi's sarcoma-associated herpesvirus (KSHV) establishes latency in B cells and is stringently linked to primary effusion lymphoma (PEL) and the premalignant B cell hyperplasia multicentric Castleman's disease (MCD). To investigate potential genetic background effects, we expressed the KSHV miRNAs in BALB/c transgenic mice. BALB/c mice are the preferred strain for B cell hybridoma development because of their propensity to develop predictable B cell responses to antigen. The BALB/c latency mice exhibited a higher incidence of B cell hyperplasia as well as sustained hyperglobulinemia. The development of neutralizing antibodies against ZIKV was augmented in BALB/c latency mice. Hyperglobulinemia was dampened by everolimus, a derivative of rapamycin, suggesting a role for mTOR inhibitors in managing immune activation, which is hallmark of KSHV infection as well as HIV infection.</AbstractText>
<CopyrightInformation>Copyright © 2018 American Society for Microbiology.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Sin</LastName>
<ForeName>Sang-Hoon</ForeName>
<Initials>SH</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, Programs in Global Oncology and Virology, Lineberger Comprehensive Cancer Center and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA sang-hoon_sin@med.unc.edu.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Eason</LastName>
<ForeName>Anthony B</ForeName>
<Initials>AB</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, Programs in Global Oncology and Virology, Lineberger Comprehensive Cancer Center and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Bigi</LastName>
<ForeName>Rachele</ForeName>
<Initials>R</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, Programs in Global Oncology and Virology, Lineberger Comprehensive Cancer Center and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Kim</LastName>
<ForeName>Yongbaek</ForeName>
<Initials>Y</Initials>
<AffiliationInfo><Affiliation>Laboratory of Veterinary Clinical Pathology, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Kang</LastName>
<ForeName>SunAh</ForeName>
<Initials>S</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, Programs in Global Oncology and Virology, Lineberger Comprehensive Cancer Center and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Tan</LastName>
<ForeName>Kelly</ForeName>
<Initials>K</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, Programs in Global Oncology and Virology, Lineberger Comprehensive Cancer Center and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Seltzer</LastName>
<ForeName>Tischan A</ForeName>
<Initials>TA</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, Programs in Global Oncology and Virology, Lineberger Comprehensive Cancer Center and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Venkataramanan</LastName>
<ForeName>Raman</ForeName>
<Initials>R</Initials>
<AffiliationInfo><Affiliation>Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>An</LastName>
<ForeName>Hyowon</ForeName>
<Initials>H</Initials>
<AffiliationInfo><Affiliation>Department of Statistics & Operations Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Dittmer</LastName>
<ForeName>Dirk P</ForeName>
<Initials>DP</Initials>
<Identifier Source="ORCID">https://orcid.org/0000-0003-4968-5656</Identifier>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, Programs in Global Oncology and Virology, Lineberger Comprehensive Cancer Center and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<GrantList CompleteYN="Y"><Grant><GrantID>P01 CA019014</GrantID>
<Acronym>CA</Acronym>
<Agency>NCI NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>P30 CA016086</GrantID>
<Acronym>CA</Acronym>
<Agency>NCI NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>R01 DE018304</GrantID>
<Acronym>DE</Acronym>
<Agency>NIDCR NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>R01 CA228172</GrantID>
<Acronym>CA</Acronym>
<Agency>NCI NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>T32 NR007091</GrantID>
<Acronym>NR</Acronym>
<Agency>NINR NIH HHS</Agency>
<Country>United States</Country>
</Grant>
</GrantList>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
<PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2018</Year>
<Month>09</Month>
<Day>12</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>J Virol</MedlineTA>
<NlmUniqueID>0113724</NlmUniqueID>
<ISSNLinking>0022-538X</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000970">Antineoplastic Agents</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C499172">Fcgr2b protein, mouse</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D007166">Immunosuppressive Agents</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D035683">MicroRNAs</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D012367">RNA, Viral</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D017452">Receptors, IgG</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D013729">Terpenes</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>26HZV48DT1</RegistryNumber>
<NameOfSubstance UI="C009042">pristane</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>9HW64Q8G6G</RegistryNumber>
<NameOfSubstance UI="D000068338">Everolimus</NameOfSubstance>
</Chemical>
</ChemicalList>
<CitationSubset>IM</CitationSubset>
<MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000970" MajorTopicYN="N">Antineoplastic Agents</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D001402" MajorTopicYN="N">B-Lymphocytes</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName>
<QualifierName UI="Q000821" MajorTopicYN="Y">virology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D002454" MajorTopicYN="N">Cell Differentiation</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D060085" MajorTopicYN="N">Coinfection</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D060467" MajorTopicYN="N">Disease Resistance</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000068338" MajorTopicYN="N">Everolimus</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D019288" MajorTopicYN="N">Herpesvirus 8, Human</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006942" MajorTopicYN="N">Hypergammaglobulinemia</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName>
<QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D007166" MajorTopicYN="N">Immunosuppressive Agents</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008807" MajorTopicYN="N">Mice, Inbred BALB C</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D018345" MajorTopicYN="N">Mice, Knockout</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008819" MajorTopicYN="N">Mice, Nude</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D035683" MajorTopicYN="N">MicroRNAs</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D010954" MajorTopicYN="N">Plasmacytoma</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName>
<QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D012367" MajorTopicYN="N">RNA, Viral</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D017452" MajorTopicYN="N">Receptors, IgG</DescriptorName>
<QualifierName UI="Q000172" MajorTopicYN="N">deficiency</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D012514" MajorTopicYN="N">Sarcoma, Kaposi</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName>
<QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D013729" MajorTopicYN="N">Terpenes</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D017735" MajorTopicYN="Y">Virus Latency</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000071244" MajorTopicYN="N">Zika Virus</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000071243" MajorTopicYN="N">Zika Virus Infection</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName>
<QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName>
</MeshHeading>
</MeshHeadingList>
<KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">KSHV</Keyword>
<Keyword MajorTopicYN="Y">Kaposi's sarcoma</Keyword>
<Keyword MajorTopicYN="Y">mouse model</Keyword>
<Keyword MajorTopicYN="Y">primary effusion lymphoma</Keyword>
<Keyword MajorTopicYN="Y">rapamycin</Keyword>
</KeywordList>
</MedlineCitation>
<PubmedData><History><PubMedPubDate PubStatus="received"><Year>2018</Year>
<Month>07</Month>
<Day>06</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="accepted"><Year>2018</Year>
<Month>07</Month>
<Day>06</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="pubmed"><Year>2018</Year>
<Month>7</Month>
<Day>20</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="medline"><Year>2018</Year>
<Month>9</Month>
<Day>19</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="entrez"><Year>2018</Year>
<Month>7</Month>
<Day>20</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
</History>
<PublicationStatus>epublish</PublicationStatus>
<ArticleIdList><ArticleId IdType="pubmed">30021906</ArticleId>
<ArticleId IdType="pii">JVI.01138-18</ArticleId>
<ArticleId IdType="doi">10.1128/JVI.01138-18</ArticleId>
<ArticleId IdType="pmc">PMC6146794</ArticleId>
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<settlement><li>Chapel Hill (Caroline du Nord)</li>
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<name sortKey="Kang, Sunah" sort="Kang, Sunah" uniqKey="Kang S" first="Sunah" last="Kang">Sunah Kang</name>
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Kaposi's Sarcoma-Associated Herpesvirus Latency Locus Renders B Cells Hyperresponsive to Secondary Infections.

Kaposi's Sarcoma-Associated Herpesvirus Latency Locus Renders B Cells Hyperresponsive to Secondary Infections.

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