Differential Immunogenicity of HIV‐1 Clade C Proteins in Eliciting CD8+ and CD4+ Cell Responses
Identifieur interne : 001520 ( Istex/Corpus ); précédent : 001519; suivant : 001521Differential Immunogenicity of HIV‐1 Clade C Proteins in Eliciting CD8+ and CD4+ Cell Responses
Auteurs : Danni Ramduth ; Polan Chetty ; Nolwandle Cyloria Mngquandaniso ; Nonhlanhla Nene ; Jason Davis Harlow ; Isobella Honeyborne ; Nelisiwe Ntumba ; Sharika Gappoo ; Chiara Henry ; Prakash Jeena ; Marylyn Martina Addo ; Marcus Altfeld ; Christian Brander ; Cheryl Day ; Hoosen Coovadia ; Photini Kiepiela ; Philip Goulder ; Bruce WalkerSource :
- Journal of Infectious Diseases [ 0022-1899 ] ; 2005.
Abstract
Background. The relative immunogenicity of human immunodeficiency virus type 1 (HIV‐1) proteins for CD8+ and CD4+ cell responses has not been defined. Methods. HIV‐1–specific T cell responses were evaluated in 65 chronically HIV‐1–infected untreated subjects by interferon‐γ flow cytometry with peptides spanning the clade C consensus sequence. Results. The magnitude of HIV‐1–specific CD8+ T cell responses correlated significantly with CD4+ cell responses, but the percentage of CD8+ T cells directed against HIV‐1 (median, 2.76%) was always greater than that of CD4+ cells (median, 0.24%). Although CD8+ T cell responses were equally distributed among Gag, Pol, and the regulatory and accessory proteins, Gag was the dominant target for CD4+ cell responses. There was no consistent relationship between virus‐specific CD8+ or CD4+ cell response and viral load. However, the median viral load in subjects in whom Gag was the dominant CD8+ T cell target was significantly lower than that in subjects in whom non‐Gag proteins were the main target (P=.007). Conclusions. Gag‐specific responses dominate the CD4+ T cell response to HIV, whereas CD8+ T cell responses are broadly distributed, which indicates differential immunogenicity of these cells against HIV‐1. The preferential targeting of Gag by CD8+ T cells is associated with enhanced control of viral load.
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DOI: 10.1086/496894
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Massachusetts;</mods:affiliation></affiliation></author><author><name sortKey="Altfeld, Marcus" sort="Altfeld, Marcus" uniqKey="Altfeld M" first="Marcus" last="Altfeld">Marcus Altfeld</name><affiliation><mods:affiliation>Partners AIDS Research Center and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;</mods:affiliation></affiliation></author><author><name sortKey="Brander, Christian" sort="Brander, Christian" uniqKey="Brander C" first="Christian" last="Brander">Christian Brander</name><affiliation><mods:affiliation>Partners AIDS Research Center and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;</mods:affiliation></affiliation></author><author><name sortKey="Day, Cheryl" sort="Day, Cheryl" uniqKey="Day C" first="Cheryl" last="Day">Cheryl Day</name><affiliation><mods:affiliation>Peter Medwar Building for Pathogen Research, Oxford University, Oxford, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Coovadia, Hoosen" sort="Coovadia, Hoosen" uniqKey="Coovadia H" first="Hoosen" last="Coovadia">Hoosen Coovadia</name><affiliation><mods:affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</mods:affiliation></affiliation></author><author><name sortKey="Kiepiela, Photini" sort="Kiepiela, Photini" uniqKey="Kiepiela P" first="Photini" last="Kiepiela">Photini Kiepiela</name><affiliation><mods:affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</mods:affiliation></affiliation></author><author><name sortKey="Goulder, Philip" sort="Goulder, Philip" uniqKey="Goulder P" first="Philip" last="Goulder">Philip Goulder</name><affiliation><mods:affiliation>Partners AIDS Research Center and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;</mods:affiliation></affiliation><affiliation><mods:affiliation>Peter Medwar Building for Pathogen Research, Oxford University, Oxford, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Walker, Bruce" sort="Walker, Bruce" uniqKey="Walker B" first="Bruce" last="Walker">Bruce Walker</name><affiliation><mods:affiliation>Partners AIDS Research Center and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:4222E856E5253B10486402C09E3F9AEA716D7F46</idno><date when="2005" year="2005">2005</date><idno type="doi">10.1086/496894</idno><idno type="url">https://api.istex.fr/ark:/67375/HXZ-RPBJ4V5V-6/fulltext.pdf</idno><idno type="wicri:Area/Istex/Corpus">001520</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">001520</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main">Differential Immunogenicity of HIV‐1 Clade C Proteins in Eliciting CD8<hi rend="superscript">+</hi> and CD4<hi rend="superscript">+</hi> Cell Responses<ref type="fn" target="#fn1"></ref></title><author><name sortKey="Ramduth, Danni" sort="Ramduth, Danni" uniqKey="Ramduth D" first="Danni" last="Ramduth">Danni Ramduth</name><affiliation><mods:affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: ramduthd1@ukzn.ac.za</mods:affiliation></affiliation></author><author><name sortKey="Chetty, Polan" sort="Chetty, Polan" uniqKey="Chetty P" first="Polan" last="Chetty">Polan Chetty</name><affiliation><mods:affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</mods:affiliation></affiliation></author><author><name sortKey="Mngquandaniso, Nolwandle Cyloria" sort="Mngquandaniso, Nolwandle Cyloria" uniqKey="Mngquandaniso N" first="Nolwandle Cyloria" last="Mngquandaniso">Nolwandle Cyloria Mngquandaniso</name><affiliation><mods:affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</mods:affiliation></affiliation></author><author><name sortKey="Nene, Nonhlanhla" sort="Nene, Nonhlanhla" uniqKey="Nene N" first="Nonhlanhla" last="Nene">Nonhlanhla Nene</name><affiliation><mods:affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</mods:affiliation></affiliation></author><author><name sortKey="Harlow, Jason Davis" sort="Harlow, Jason Davis" uniqKey="Harlow J" first="Jason Davis" last="Harlow">Jason Davis Harlow</name><affiliation><mods:affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</mods:affiliation></affiliation></author><author><name sortKey="Honeyborne, Isobella" sort="Honeyborne, Isobella" uniqKey="Honeyborne I" first="Isobella" last="Honeyborne">Isobella Honeyborne</name><affiliation><mods:affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</mods:affiliation></affiliation></author><author><name sortKey="Ntumba, Nelisiwe" sort="Ntumba, Nelisiwe" uniqKey="Ntumba N" first="Nelisiwe" last="Ntumba">Nelisiwe Ntumba</name><affiliation><mods:affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</mods:affiliation></affiliation></author><author><name sortKey="Gappoo, Sharika" sort="Gappoo, Sharika" uniqKey="Gappoo S" first="Sharika" last="Gappoo">Sharika Gappoo</name><affiliation><mods:affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</mods:affiliation></affiliation></author><author><name sortKey="Henry, Chiara" sort="Henry, Chiara" uniqKey="Henry C" first="Chiara" last="Henry">Chiara Henry</name><affiliation><mods:affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</mods:affiliation></affiliation></author><author><name sortKey="Jeena, Prakash" sort="Jeena, Prakash" uniqKey="Jeena P" first="Prakash" last="Jeena">Prakash Jeena</name><affiliation><mods:affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</mods:affiliation></affiliation></author><author><name sortKey="Addo, Marylyn Martina" sort="Addo, Marylyn Martina" uniqKey="Addo M" first="Marylyn Martina" last="Addo">Marylyn Martina Addo</name><affiliation><mods:affiliation>Partners AIDS Research Center and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;</mods:affiliation></affiliation></author><author><name sortKey="Altfeld, Marcus" sort="Altfeld, Marcus" uniqKey="Altfeld M" first="Marcus" last="Altfeld">Marcus Altfeld</name><affiliation><mods:affiliation>Partners AIDS Research Center and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;</mods:affiliation></affiliation></author><author><name sortKey="Brander, Christian" sort="Brander, Christian" uniqKey="Brander C" first="Christian" last="Brander">Christian Brander</name><affiliation><mods:affiliation>Partners AIDS Research Center and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;</mods:affiliation></affiliation></author><author><name sortKey="Day, Cheryl" sort="Day, Cheryl" uniqKey="Day C" first="Cheryl" last="Day">Cheryl Day</name><affiliation><mods:affiliation>Peter Medwar Building for Pathogen Research, Oxford University, Oxford, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Coovadia, Hoosen" sort="Coovadia, Hoosen" uniqKey="Coovadia H" first="Hoosen" last="Coovadia">Hoosen Coovadia</name><affiliation><mods:affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</mods:affiliation></affiliation></author><author><name sortKey="Kiepiela, Photini" sort="Kiepiela, Photini" uniqKey="Kiepiela P" first="Photini" last="Kiepiela">Photini Kiepiela</name><affiliation><mods:affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</mods:affiliation></affiliation></author><author><name sortKey="Goulder, Philip" sort="Goulder, Philip" uniqKey="Goulder P" first="Philip" last="Goulder">Philip Goulder</name><affiliation><mods:affiliation>Partners AIDS Research Center and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;</mods:affiliation></affiliation><affiliation><mods:affiliation>Peter Medwar Building for Pathogen Research, Oxford University, Oxford, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Walker, Bruce" sort="Walker, Bruce" uniqKey="Walker B" first="Bruce" last="Walker">Bruce Walker</name><affiliation><mods:affiliation>Partners AIDS Research Center and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Journal of Infectious Diseases</title><title level="j" type="abbrev">J Infect Dis.</title><idno type="ISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><publisher>The University of Chicago Press</publisher><date type="published">2005</date><biblScope unit="vol">192</biblScope><biblScope unit="issue">9</biblScope><biblScope unit="page" from="1588">1588</biblScope><biblScope unit="page" to="1596">1596</biblScope></imprint><idno type="ISSN">0022-1899</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-1899</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Background. The relative immunogenicity of human immunodeficiency virus type 1 (HIV‐1) proteins for CD8+ and CD4+ cell responses has not been defined. Methods. HIV‐1–specific T cell responses were evaluated in 65 chronically HIV‐1–infected untreated subjects by interferon‐γ flow cytometry with peptides spanning the clade C consensus sequence. Results. The magnitude of HIV‐1–specific CD8+ T cell responses correlated significantly with CD4+ cell responses, but the percentage of CD8+ T cells directed against HIV‐1 (median, 2.76%) was always greater than that of CD4+ cells (median, 0.24%). Although CD8+ T cell responses were equally distributed among Gag, Pol, and the regulatory and accessory proteins, Gag was the dominant target for CD4+ cell responses. There was no consistent relationship between virus‐specific CD8+ or CD4+ cell response and viral load. However, the median viral load in subjects in whom Gag was the dominant CD8+ T cell target was significantly lower than that in subjects in whom non‐Gag proteins were the main target (P=.007). Conclusions. Gag‐specific responses dominate the CD4+ T cell response to HIV, whereas CD8+ T cell responses are broadly distributed, which indicates differential immunogenicity of these cells against HIV‐1. The preferential targeting of Gag by CD8+ T cells is associated with enhanced control of viral load.</div></front></TEI><istex><corpusName>oup</corpusName><keywords><teeft><json:string>cell response</json:string><json:string>viral</json:string><json:string>clade</json:string><json:string>viral load</json:string><json:string>cohort</json:string><json:string>gure</json:string><json:string>virol</json:string><json:string>ntrvvv</json:string><json:string>immune</json:string><json:string>human virus type</json:string><json:string>november</json:string><json:string>median</json:string><json:string>peptide</json:string><json:string>durban</json:string><json:string>lymphocyte</json:string><json:string>pbmcs</json:string><json:string>cytotoxic</json:string><json:string>datum</json:string><json:string>cell activity</json:string><json:string>lower viral load</json:string><json:string>positive correlation</json:string><json:string>assay</json:string><json:string>threshold ratio</json:string><json:string>consensus sequence</json:string><json:string>median viral load</json:string><json:string>acute infection</json:string><json:string>cell target</json:string><json:string>negative control</json:string><json:string>chronic viral infection</json:string><json:string>absolute number</json:string><json:string>peptide pool</json:string><json:string>present study</json:string><json:string>becton dickinson</json:string><json:string>individual subject</json:string><json:string>nonpregnant woman</json:string><json:string>positive association</json:string><json:string>chronic infection</json:string><json:string>viral control</json:string><json:string>doris duke medical research institute</json:string><json:string>cell memory</json:string><json:string>infection</json:string></teeft></keywords><author><json:item><name>Danni Ramduth</name><affiliations><json:string>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</json:string><json:string>E-mail: ramduthd1@ukzn.ac.za</json:string></affiliations></json:item><json:item><name>Polan Chetty</name><affiliations><json:string>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</json:string></affiliations></json:item><json:item><name>Nolwandle Cyloria Mngquandaniso</name><affiliations><json:string>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</json:string></affiliations></json:item><json:item><name>Nonhlanhla Nene</name><affiliations><json:string>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</json:string></affiliations></json:item><json:item><name>Jason Davis Harlow</name><affiliations><json:string>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</json:string></affiliations></json:item><json:item><name>Isobella Honeyborne</name><affiliations><json:string>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</json:string></affiliations></json:item><json:item><name>Nelisiwe Ntumba</name><affiliations><json:string>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</json:string></affiliations></json:item><json:item><name>Sharika Gappoo</name><affiliations><json:string>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</json:string></affiliations></json:item><json:item><name>Chiara Henry</name><affiliations><json:string>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</json:string></affiliations></json:item><json:item><name>Prakash Jeena</name><affiliations><json:string>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</json:string></affiliations></json:item><json:item><name>Marylyn Martina Addo</name><affiliations><json:string>Partners AIDS Research Center and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;</json:string></affiliations></json:item><json:item><name>Marcus Altfeld</name><affiliations><json:string>Partners AIDS Research Center and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;</json:string></affiliations></json:item><json:item><name>Christian Brander</name><affiliations><json:string>Partners AIDS Research Center and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;</json:string></affiliations></json:item><json:item><name>Cheryl Day</name><affiliations><json:string>Peter Medwar Building for Pathogen Research, Oxford University, Oxford, United Kingdom</json:string></affiliations></json:item><json:item><name>Hoosen Coovadia</name><affiliations><json:string>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</json:string></affiliations></json:item><json:item><name>Photini Kiepiela</name><affiliations><json:string>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</json:string></affiliations></json:item><json:item><name>Philip Goulder</name><affiliations><json:string>Partners AIDS Research Center and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;</json:string><json:string>Peter Medwar Building for Pathogen Research, Oxford University, Oxford, United Kingdom</json:string></affiliations></json:item><json:item><name>Bruce Walker</name><affiliations><json:string>Partners AIDS Research Center and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;</json:string></affiliations></json:item></author><arkIstex>ark:/67375/HXZ-RPBJ4V5V-6</arkIstex><language><json:string>unknown</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>Background. The relative immunogenicity of human immunodeficiency virus type 1 (HIV‐1) proteins for CD8+ and CD4+ cell responses has not been defined. Methods. HIV‐1–specific T cell responses were evaluated in 65 chronically HIV‐1–infected untreated subjects by interferon‐γ flow cytometry with peptides spanning the clade C consensus sequence. Results. The magnitude of HIV‐1–specific CD8+ T cell responses correlated significantly with CD4+ cell responses, but the percentage of CD8+ T cells directed against HIV‐1 (median, 2.76%) was always greater than that of CD4+ cells (median, 0.24%). Although CD8+ T cell responses were equally distributed among Gag, Pol, and the regulatory and accessory proteins, Gag was the dominant target for CD4+ cell responses. There was no consistent relationship between virus‐specific CD8+ or CD4+ cell response and viral load. However, the median viral load in subjects in whom Gag was the dominant CD8+ T cell target was significantly lower than that in subjects in whom non‐Gag proteins were the main target (P=.007). Conclusions. Gag‐specific responses dominate the CD4+ T cell response to HIV, whereas CD8+ T cell responses are broadly distributed, which indicates differential immunogenicity of these cells against HIV‐1. The preferential targeting of Gag by CD8+ T cells is associated with enhanced control of viral load.</abstract><qualityIndicators><score>8.103</score><pdfWordCount>5213</pdfWordCount><pdfCharCount>30962</pdfCharCount><pdfVersion>1.4</pdfVersion><pdfPageCount>9</pdfPageCount><pdfPageSize>612 x 792 pts (letter)</pdfPageSize><pdfWordsPerPage>579</pdfWordsPerPage><pdfText>true</pdfText><refBibsNative>true</refBibsNative><abstractWordCount>203</abstractWordCount><abstractCharCount>1364</abstractCharCount><keywordCount>0</keywordCount></qualityIndicators><title>Differential Immunogenicity of HIV‐1 Clade C Proteins in Eliciting CD8+ and CD4+ Cell Responses</title><pmid><json:string>16206073</json:string></pmid><genre><json:string>research-article</json:string></genre><host><title>Journal of Infectious Diseases</title><language><json:string>unknown</json:string></language><issn><json:string>0022-1899</json:string></issn><eissn><json:string>1537-6613</json:string></eissn><publisherId><json:string>jid</json:string></publisherId><volume>192</volume><issue>9</issue><pages><first>1588</first><last>1596</last></pages><genre><json:string>journal</json:string></genre></host><namedEntities><unitex><date><json:string>2005</json:string><json:string>2001</json:string></date><geogName></geogName><orgName><json:string>Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts</json:string><json:string>ChemTech</json:string><json:string>Doris Duke Medical Research Institute</json:string><json:string>Sinikithemba Care Center</json:string><json:string>Hospital</json:string><json:string>Pathogen Research, Oxford University, Oxford, United Kingdom Background</json:string><json:string>AIDS Research Center and Howard Hughes</json:string></orgName><orgName_funder></orgName_funder><orgName_provider></orgName_provider><persName><json:string>Jason Davis</json:string><json:string>Bruce Walker</json:string><json:string>Marcus Altfeld</json:string><json:string>Christian Brander</json:string><json:string>Philip Goulder</json:string><json:string>Institutional</json:string><json:string>King Edward</json:string><json:string>Marylyn Martina</json:string><json:string>Cheryl Day</json:string><json:string>Chiara Henry</json:string></persName><placeName><json:string>Durban</json:string><json:string>Harlow</json:string><json:string>South Africa</json:string><json:string>Mandela</json:string></placeName><ref_url></ref_url><ref_bibl><json:string>Ramduth et al.</json:string><json:string>[5, 15, 27, 30]</json:string><json:string>[21]</json:string><json:string>[16, 19, 22]</json:string><json:string>[31]</json:string><json:string>Masemola et al. [18]</json:string><json:string>[7, 8]</json:string><json:string>[9, 10]</json:string><json:string>[19, 22]</json:string><json:string>[19]</json:string></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/HXZ-RPBJ4V5V-6</json:string></ark><categories><wos><json:string>1 - science</json:string><json:string>2 - microbiology</json:string><json:string>2 - infectious diseases</json:string><json:string>2 - immunology</json:string></wos><scienceMetrix><json:string>1 - health sciences</json:string><json:string>2 - biomedical research</json:string><json:string>3 - microbiology</json:string></scienceMetrix><scopus><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Infectious Diseases</json:string><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Immunology and Allergy</json:string></scopus><inist><json:string>1 - sciences appliquees, technologies et medecines</json:string><json:string>2 - sciences biologiques et medicales</json:string><json:string>3 - sciences medicales</json:string></inist></categories><publicationDate>2005</publicationDate><copyrightDate>2005</copyrightDate><doi><json:string>10.1086/496894</json:string></doi><id>4222E856E5253B10486402C09E3F9AEA716D7F46</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-RPBJ4V5V-6/fulltext.pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-RPBJ4V5V-6/bundle.zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/ark:/67375/HXZ-RPBJ4V5V-6/fulltext.tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main">Differential Immunogenicity of HIV‐1 Clade C Proteins in Eliciting CD8<hi rend="superscript">+</hi> and CD4<hi rend="superscript">+</hi> Cell Responses<ref type="fn" target="#fn1"></ref></title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>The University of Chicago Press</publisher><availability><licence>© 2005 by the Infectious Diseases Society of America. All rights reserved.</licence></availability><date type="Copyright" when="2005">2005</date><date type="published">2005</date></publicationStmt><notesStmt><note type="content-type" source="research-article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</note><note type="publication-type" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="article"><analytic><title level="a" type="main">Differential Immunogenicity of HIV‐1 Clade C Proteins in Eliciting CD8<hi rend="superscript">+</hi> and CD4<hi rend="superscript">+</hi> Cell Responses<ref type="fn" target="#fn1"></ref></title><author xml:id="author-0000" role="corresp"><persName><surname>Ramduth</surname><forename type="first">Danni </forename></persName><affiliation><orgName type="group">HIV Pathogenesis Programme</orgName><orgName type="institution">Doris Duke Medical Research Institute</orgName><orgName type="institution">University of KwaZulu‐Natal</orgName><address><addrLine>Durban</addrLine><addrLine>South Africa</addrLine></address></affiliation></author><author xml:id="author-0001"><persName><surname>Chetty</surname><forename type="first">Polan </forename></persName><affiliation><orgName type="group">HIV Pathogenesis Programme</orgName><orgName type="institution">Doris Duke Medical Research Institute</orgName><orgName type="institution">University of KwaZulu‐Natal</orgName><address><addrLine>Durban</addrLine><addrLine>South Africa</addrLine></address></affiliation></author><author xml:id="author-0002"><persName><surname>Mngquandaniso</surname><forename type="first">Nolwandle Cyloria </forename></persName><affiliation><orgName type="group">HIV Pathogenesis Programme</orgName><orgName type="institution">Doris Duke Medical Research Institute</orgName><orgName type="institution">University of KwaZulu‐Natal</orgName><address><addrLine>Durban</addrLine><addrLine>South Africa</addrLine></address></affiliation></author><author xml:id="author-0003"><persName><surname>Nene</surname><forename type="first">Nonhlanhla </forename></persName><affiliation><orgName type="group">HIV Pathogenesis Programme</orgName><orgName type="institution">Doris Duke Medical Research Institute</orgName><orgName type="institution">University of KwaZulu‐Natal</orgName><address><addrLine>Durban</addrLine><addrLine>South Africa</addrLine></address></affiliation></author><author xml:id="author-0004"><persName><surname>Harlow</surname><forename type="first">Jason Davis </forename></persName><affiliation><orgName type="group">HIV Pathogenesis Programme</orgName><orgName type="institution">Doris Duke Medical Research Institute</orgName><orgName type="institution">University of KwaZulu‐Natal</orgName><address><addrLine>Durban</addrLine><addrLine>South Africa</addrLine></address></affiliation></author><author xml:id="author-0005"><persName><surname>Honeyborne</surname><forename type="first">Isobella </forename></persName><affiliation><orgName type="group">HIV Pathogenesis Programme</orgName><orgName type="institution">Doris Duke Medical Research Institute</orgName><orgName type="institution">University of KwaZulu‐Natal</orgName><address><addrLine>Durban</addrLine><addrLine>South Africa</addrLine></address></affiliation></author><author xml:id="author-0006"><persName><surname>Ntumba</surname><forename type="first">Nelisiwe </forename></persName><affiliation><orgName type="group">HIV Pathogenesis Programme</orgName><orgName type="institution">Doris Duke Medical Research Institute</orgName><orgName type="institution">University of KwaZulu‐Natal</orgName><address><addrLine>Durban</addrLine><addrLine>South Africa</addrLine></address></affiliation></author><author xml:id="author-0007"><persName><surname>Gappoo</surname><forename type="first">Sharika </forename></persName><affiliation><orgName type="group">HIV Pathogenesis Programme</orgName><orgName type="institution">Doris Duke Medical Research Institute</orgName><orgName type="institution">University of KwaZulu‐Natal</orgName><address><addrLine>Durban</addrLine><addrLine>South Africa</addrLine></address></affiliation></author><author xml:id="author-0008"><persName><surname>Henry</surname><forename type="first">Chiara </forename></persName><affiliation><orgName type="group">HIV Pathogenesis Programme</orgName><orgName type="institution">Doris Duke Medical Research Institute</orgName><orgName type="institution">University of KwaZulu‐Natal</orgName><address><addrLine>Durban</addrLine><addrLine>South Africa</addrLine></address></affiliation></author><author xml:id="author-0009"><persName><surname>Jeena</surname><forename type="first">Prakash </forename></persName><affiliation><orgName type="group">HIV Pathogenesis Programme</orgName><orgName type="institution">Doris Duke Medical Research Institute</orgName><orgName type="institution">University of KwaZulu‐Natal</orgName><address><addrLine>Durban</addrLine><addrLine>South Africa</addrLine></address></affiliation></author><author xml:id="author-0010"><persName><surname>Addo</surname><forename type="first">Marylyn Martina </forename></persName><affiliation><orgName type="institution">Partners AIDS Research Center and Howard Hughes Medical Institute</orgName><orgName type="institution">Massachusetts General Hospital and Harvard Medical School</orgName><address><addrLine>Boston</addrLine><addrLine>Massachusetts</addrLine></address></affiliation></author><author xml:id="author-0011"><persName><surname>Altfeld</surname><forename type="first">Marcus </forename></persName><affiliation><orgName type="institution">Partners AIDS Research Center and Howard Hughes Medical Institute</orgName><orgName type="institution">Massachusetts General Hospital and Harvard Medical School</orgName><address><addrLine>Boston</addrLine><addrLine>Massachusetts</addrLine></address></affiliation></author><author xml:id="author-0012"><persName><surname>Brander</surname><forename type="first">Christian </forename></persName><affiliation><orgName type="institution">Partners AIDS Research Center and Howard Hughes Medical Institute</orgName><orgName type="institution">Massachusetts General Hospital and Harvard Medical School</orgName><address><addrLine>Boston</addrLine><addrLine>Massachusetts</addrLine></address></affiliation></author><author xml:id="author-0013"><persName><surname>Day</surname><forename type="first">Cheryl </forename></persName><affiliation><orgName type="laboratory">Peter Medwar Building for Pathogen Research</orgName><orgName type="institution">Oxford University</orgName><address><addrLine>Oxford</addrLine><addrLine>United Kingdom</addrLine></address></affiliation></author><author xml:id="author-0014"><persName><surname>Coovadia</surname><forename type="first">Hoosen </forename></persName><affiliation><orgName type="group">HIV Pathogenesis Programme</orgName><orgName type="institution">Doris Duke Medical Research Institute</orgName><orgName type="institution">University of KwaZulu‐Natal</orgName><address><addrLine>Durban</addrLine><addrLine>South Africa</addrLine></address></affiliation></author><author xml:id="author-0015"><persName><surname>Kiepiela</surname><forename type="first">Photini </forename></persName><affiliation><orgName type="group">HIV Pathogenesis Programme</orgName><orgName type="institution">Doris Duke Medical Research Institute</orgName><orgName type="institution">University of KwaZulu‐Natal</orgName><address><addrLine>Durban</addrLine><addrLine>South Africa</addrLine></address></affiliation></author><author xml:id="author-0016"><persName><surname>Goulder</surname><forename type="first">Philip </forename></persName><affiliation><orgName type="institution">Partners AIDS Research Center and Howard Hughes Medical Institute</orgName><orgName type="institution">Massachusetts General Hospital and Harvard Medical School</orgName><address><addrLine>Boston</addrLine><addrLine>Massachusetts</addrLine></address></affiliation><affiliation><orgName type="laboratory">Peter Medwar Building for Pathogen Research</orgName><orgName type="institution">Oxford University</orgName><address><addrLine>Oxford</addrLine><addrLine>United Kingdom</addrLine></address></affiliation></author><author xml:id="author-0017"><persName><surname>Walker</surname><forename type="first">Bruce </forename></persName><affiliation><orgName type="institution">Partners AIDS Research Center and Howard Hughes Medical Institute</orgName><orgName type="institution">Massachusetts General Hospital and Harvard Medical School</orgName><address><addrLine>Boston</addrLine><addrLine>Massachusetts</addrLine></address></affiliation></author><idno type="istex">4222E856E5253B10486402C09E3F9AEA716D7F46</idno><idno type="ark">ark:/67375/HXZ-RPBJ4V5V-6</idno><idno type="DOI">10.1086/496894</idno></analytic><monogr><title level="j" type="main">Journal of Infectious Diseases</title><title level="j" type="abbrev">J Infect Dis.</title><idno type="hwp">jinfdis</idno><idno type="publisher-id">jid</idno><idno type="pISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><publisher>The University of Chicago Press</publisher><date type="published">2005</date><biblScope unit="vol">192</biblScope><biblScope unit="issue">9</biblScope><biblScope unit="page" from="1588">1588</biblScope><biblScope unit="page" to="1596">1596</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><encodingDesc><schemaRef type="ODD" url="https://xml-schema.delivery.istex.fr/tei-istex.odd"></schemaRef><appInfo><application ident="pub2tei" version="1.0.41" when="2020-04-06"><label>pub2TEI-ISTEX</label><desc>A set of style sheets for converting XML documents encoded in various scientific publisher formats into a common TEI format.
<ref target="http://www.tei-c.org/">We use TEI</ref></desc></application></appInfo></encodingDesc><profileDesc><abstract><p><hi rend="bold">Background. </hi>The relative immunogenicity of human immunodeficiency virus type 1 (HIV‐1) proteins for CD8<hi rend="superscript">+</hi> and CD4<hi rend="superscript">+</hi> cell responses has not been defined.</p><p><hi rend="bold">Methods. </hi>HIV‐1–specific T cell responses were evaluated in 65 chronically HIV‐1–infected untreated subjects by interferon‐γ flow cytometry with peptides spanning the clade C consensus sequence.</p><p><hi rend="bold">Results. </hi>The magnitude of HIV‐1–specific CD8<hi rend="superscript">+</hi> T cell responses correlated significantly with CD4<hi rend="superscript">+</hi> cell responses, but the percentage of CD8<hi rend="superscript">+</hi> T cells directed against HIV‐1 (median, 2.76%) was always greater than that of CD4<hi rend="superscript">+</hi> cells (median, 0.24%). Although CD8<hi rend="superscript">+</hi> T cell responses were equally distributed among Gag, Pol, and the regulatory and accessory proteins, Gag was the dominant target for CD4<hi rend="superscript">+</hi> cell responses. There was no consistent relationship between virus‐specific CD8<hi rend="superscript">+</hi> or CD4<hi rend="superscript">+</hi> cell response and viral load. However, the median viral load in subjects in whom Gag was the dominant CD8<hi rend="superscript">+</hi> T cell target was significantly lower than that in subjects in whom non‐Gag proteins were the main target (<formula rend="inline">P=.007</formula>).</p><p><hi rend="bold">Conclusions. </hi>Gag‐specific responses dominate the CD4<hi rend="superscript">+</hi> T cell response to HIV, whereas CD8<hi rend="superscript">+</hi> T cell responses are broadly distributed, which indicates differential immunogenicity of these cells against HIV‐1. The preferential targeting of Gag by CD8<hi rend="superscript">+</hi> T cells is associated with enhanced control of viral load.</p></abstract><textClass ana="subject"><keywords scheme="heading"><term>Major Articles and Brief Reports</term></keywords></textClass><langUsage><language ident="EN"></language></langUsage></profileDesc><revisionDesc><change when="2020-04-06" who="#istex" xml:id="pub2tei">formatting</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-RPBJ4V5V-6/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup, element #text not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article">
<front>
<journal-meta>
<journal-id journal-id-type="hwp">jinfdis</journal-id>
<journal-id journal-id-type="publisher-id">jid</journal-id>
<journal-title>Journal of Infectious Diseases</journal-title>
<abbrev-journal-title>J Infect Dis.</abbrev-journal-title>
<issn pub-type="ppub">0022-1899</issn>
<issn pub-type="epub">1537-6613</issn>
<publisher>
<publisher-name>The University of Chicago Press</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.1086/496894</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Major Articles and Brief Reports</subject>
<subj-group subj-group-type="heading">
<subject>HIV/AIDS</subject>
<subj-group subj-group-type="heading">
<subject>Major Articles</subject>
</subj-group>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Differential Immunogenicity of HIV‐1 Clade C Proteins in Eliciting CD8<sup>+</sup> and CD4<sup>+</sup> Cell Responses<xref ref-type="fn" rid="fn1"></xref></article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Ramduth</surname>
<given-names>Danni </given-names></name><xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Chetty</surname>
<given-names>Polan </given-names></name><xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Mngquandaniso</surname>
<given-names>Nolwandle Cyloria </given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="fn" rid="fn2">a</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Nene</surname>
<given-names>Nonhlanhla </given-names></name><xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Harlow</surname>
<given-names>Jason Davis </given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="fn" rid="fn2">a</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Honeyborne</surname>
<given-names>Isobella </given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="fn" rid="fn2">a</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Ntumba</surname>
<given-names>Nelisiwe </given-names></name><xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Gappoo</surname>
<given-names>Sharika </given-names></name><xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Henry</surname>
<given-names>Chiara </given-names></name><xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Jeena</surname>
<given-names>Prakash </given-names></name><xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Addo</surname>
<given-names>Marylyn Martina </given-names></name><xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Altfeld</surname>
<given-names>Marcus </given-names></name><xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Brander</surname>
<given-names>Christian </given-names></name><xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Day</surname>
<given-names>Cheryl </given-names></name><xref ref-type="aff" rid="aff3">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Coovadia</surname>
<given-names>Hoosen </given-names></name><xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Kiepiela</surname>
<given-names>Photini </given-names></name><xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Goulder</surname>
<given-names>Philip </given-names></name><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff3">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Walker</surname>
<given-names>Bruce </given-names></name><xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<aff id="aff1">
<label>1</label>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</aff>
<aff id="aff2">
<label>2</label>Partners AIDS Research Center and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;</aff>
<aff id="aff3">
<label>3</label>Peter Medwar Building for Pathogen Research, Oxford University, Oxford, United Kingdom</aff>
</contrib-group>
<author-notes>
<corresp>Reprints or correspondence: Dr. Danni Ramduth, HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu‐Natal, Durban, South Africa (<email>ramduthd1@ukzn.ac.za</email>).</corresp>
</author-notes>
<pub-date pub-type="ppub">
<day>1</day>
<month>11</month>
<year>2005</year>
</pub-date>
<volume>192</volume>
<issue>9</issue>
<fpage>1588</fpage>
<lpage>1596</lpage>
<history>
<date date-type="received">
<day>29</day>
<month>3</month>
<year>2005</year></date>
<date date-type="accepted">
<day>1</day>
<month>6</month>
<year>2005</year></date>
</history>
<copyright-statement>© 2005 by the Infectious Diseases Society of America. All rights reserved.</copyright-statement>
<copyright-year>2005</copyright-year>
<abstract>
<p><bold>Background. </bold>The relative immunogenicity of human immunodeficiency virus type 1 (HIV‐1) proteins for CD8<sup>+</sup> and CD4<sup>+</sup> cell responses has not been defined.</p>
<p><bold>Methods. </bold>HIV‐1–specific T cell responses were evaluated in 65 chronically HIV‐1–infected untreated subjects by interferon‐γ flow cytometry with peptides spanning the clade C consensus sequence.</p>
<p><bold>Results. </bold>The magnitude of HIV‐1–specific CD8<sup>+</sup> T cell responses correlated significantly with CD4<sup>+</sup> cell responses, but the percentage of CD8<sup>+</sup> T cells directed against HIV‐1 (median, 2.76%) was always greater than that of CD4<sup>+</sup> cells (median, 0.24%). Although CD8<sup>+</sup> T cell responses were equally distributed among Gag, Pol, and the regulatory and accessory proteins, Gag was the dominant target for CD4<sup>+</sup> cell responses. There was no consistent relationship between virus‐specific CD8<sup>+</sup> or CD4<sup>+</sup> cell response and viral load. However, the median viral load in subjects in whom Gag was the dominant CD8<sup>+</sup> T cell target was significantly lower than that in subjects in whom non‐Gag proteins were the main target (<inline-formula>P=.007</inline-formula>).</p>
<p><bold>Conclusions. </bold>Gag‐specific responses dominate the CD4<sup>+</sup> T cell response to HIV, whereas CD8<sup>+</sup> T cell responses are broadly distributed, which indicates differential immunogenicity of these cells against HIV‐1. The preferential targeting of Gag by CD8<sup>+</sup> T cells is associated with enhanced control of viral load.</p>
</abstract>
</article-meta>
</front>
<body>
<p>Effective immune control in animal models of chronic viral infections is associated with an adaptive immune response that includes CD4<sup>+</sup> and CD8<sup>+</sup> cell responses. The preferential infection of activated CD4<sup>+</sup> lymphocytes by HIV‐1 is thought to lead to the collapse of the human immune system and the lack of control of opportunistic infections that characterize AIDS [<xref ref-type="bibr" rid="ref1">1</xref>, <xref ref-type="bibr" rid="ref2">2</xref>]. However, despite the extensive loss of CD4<sup>+</sup>CCR5<sup>+</sup> cells in the gut during the earliest stages of acute infection and the progressive depletion of peripheral CD4<sup>+</sup> cells [<xref ref-type="bibr" rid="ref3">3</xref>, <xref ref-type="bibr" rid="ref4">4</xref>] virus‐specific CD4<sup>+</sup> cells that produce interferon (IFN)–γ do persist in most chronically infected subjects, although with a reduced proliferative capacity [<xref ref-type="bibr" rid="ref5">5</xref>, <xref ref-type="bibr" rid="ref6">6</xref>].</p>
<p>Despite the persistence of CD8<sup>+</sup> T cell activity against HIV‐1, the majority of infected subjects have progressive uncontrolled viral loads and eventually develop AIDS [<xref ref-type="bibr" rid="ref7">7</xref>, <xref ref-type="bibr" rid="ref8">8</xref>]. This implies that CD8<sup>+</sup> T cells alone cannot suppress HIV‐1 infection adequately and suggests a functional impairment of these cells [<xref ref-type="bibr" rid="ref9">9</xref>, <xref ref-type="bibr" rid="ref10">10</xref>]. Evidence from studies of lymphocytic choriomeningitis virus infection in mice and HIV‐1 clade B infection in humans have suggested that the long‐term maintenance of effective cytotoxic T lymphocyte activity is dependent on the presence of functional CD4<sup>+</sup> cells [<xref ref-type="bibr" rid="ref11">11</xref><xref ref-type="bibr" rid="ref12"></xref><xref ref-type="bibr" rid="ref13"></xref><xref ref-type="bibr" rid="ref14"></xref>–<xref ref-type="bibr" rid="ref15">15</xref>] .</p>
<p>The brunt of the AIDS epidemic is borne by sub‐Saharan Africa, where the majority of HIV‐1 infections are caused by clade C virus. The few immunologic studies that have focused on clade C infection have comprehensively analyzed total T cell responses against HIV‐1, without differentiating between CD8<sup>+</sup> and CD4<sup>+</sup> cell responses [<xref ref-type="bibr" rid="ref16">16</xref><xref ref-type="bibr" rid="ref17"></xref><xref ref-type="bibr" rid="ref18"></xref>–<xref ref-type="bibr" rid="ref19">19</xref>]. Studies that have examined CD4<sup>+</sup> helper cell responses in South Africans have been limited to chronically infected children, and they have used less‐sensitive assays, such as lymphocyte proliferation and ELISA [<xref ref-type="bibr" rid="ref20">20</xref>]. In the present study, we performed a simultaneous and comprehensive quantitation of both CD8<sup>+</sup> and CD4<sup>+</sup> cell responses to the entire HIV‐1 clade C proteome in infected adults.</p>
<p>Our results indicate that the majority of persons chronically infected with clade C virus maintain HIV‐specific CD8<sup>+</sup> and CD4<sup>+</sup> cells that produce IFN‐γ. This response is consistently dominated by HIV‐1–specific CD8<sup>+</sup> cells, with the absolute number of HIV‐1–specific CD8<sup>+</sup> T cells being >10‐fold higher than that of HIV‐1–specific CD4<sup>+</sup> cells. Despite a significant positive correlation between HIV‐1–specific CD8<sup>+</sup> and CD4<sup>+</sup> cell activity, there was no threshold ratio of responses that was associated with immune containment. However, the preferential targeting of Gag by CD8<sup>+</sup> T cells was associated with enhanced control of viral load, which indicates that Gag is an important target for both CD4<sup>+</sup> and CD8<sup>+</sup> cells.</p>
<sec id="S1">
<title>Subjects, Materials, and Methods</title>
<p><bold><italic>Subjects. </italic></bold>Sixty‐five HIV‐1–infected women were recruited from the Ekuphileni Cato Manor antenatal clinic and the HIV Paediatric Respiratory Clinic at King Edward VIII Hospital (both in Durban, South Africa). Five subjects were pregnant at the time of phlebotomy, and 60 were 3–24 months postdelivery. An additional 138 HIV‐1–infected pregnant women were recruited from St. Mary’s Hospital in Durban. The HIV status of the subjects was determined by an HIV‐1 ELISA, and viral load was measured as plasma HIV‐1 RNA level by use of the Roche Amplicor assay (version 1.5). The median viral loads were 17,000 and 32,800 RNA copies/mL of plasma for the respective cohorts; the median CD4<sup>+</sup> cell counts were 433 and 456 cells/μL of whole blood. Seven HIV‐1–seronegative nonpregnant subjects, as determined by a negative HIV‐1 ELISA and an undetectable viral load (<400 RNA copies/mL of plasma), were included as control subjects. An additional cohort of 160 chronically infected subjects (men and nonpregnant women) attending the Sinikithemba Care Center at the McCord Hospital in Durban was also recruited. The median viral load and CD4<sup>+</sup> cell count of this cohort was 72,100 RNA copies/mL of plasma and 315 cells/μL of whole blood. Sequence analysis completed on a random sample of 256 subjects found 96% to be infected with the HIV‐1 clade C strain. Institutional review boards reviewed the study protocol, and appropriate signed consent was obtained from all study subjects.</p>
<p><bold><italic>Synthetic HIV‐1 peptides. </italic></bold>A total of 410 overlapping peptides (15–18‐mers with a 10‐aa overlap) spanning the entire HIV‐1 clade C consensus sequences of Gag (p15, p17, and p24); Pol (integrase, protease, and reverse transcriptase); Env (gp120 and gp41); and Nef, Tat, Rev, Vpr, Vpu, and Vif (NTRVVV) were synthesized on an automated peptide synthesizer (MBS 396; Advanced ChemTech). Peptides were pooled, with pools composed of the following numbers of peptides: Gag, 66; NTRVVV, 98; Pol, 133; and Env, 113. The final concentration of each peptide within the pool used in the assay was 2 μg/mL, and sequences were based on the 2001 clade C consensus sequence [<xref ref-type="bibr" rid="ref21">21</xref>].</p>
<p><bold><italic>Lymphocyte isolation and flow‐based intracellular cytokine staining (ICS). </italic></bold>A sample of 16 mL of heparinized blood was obtained from each subject, and these were processed at the Doris Duke Medical Research Institute at the Nelson R. Mandela School of Medicine in Durban. Peripheral blood mononuclear cells (PBMCs) were isolated on a ficoll‐hypaque density‐gradient device (Sigma) within 4 h of obtaining the sample. An ICS assay for IFN‐γ was performed by use of a FACSCalibur Flow Cytometer (Becton Dickinson): PBMCs (0.5 × 10<sup>6</sup>) were incubated for 90 min with 10 μL of HIV‐1 clade C overlapping peptide pools. Brefeldin A was added, and the cells were incubated for an additional 4.5 h. Then, the cells were stained with anti–human allophycocyanin–conjugated CD4<sup>+</sup> and anti–human phycoerythrin–conjugated CD8<sup>+</sup> antibodies (Becton Dickinson), washed, fixed, and permeabilized (Caltag Reagents A and B; Caltag). Then, 15 μL of fluorescein isothiocyanate–conjugated anti–human IFN‐γ antibody was added, and the cells were incubated for 30 min before they were washed and analyzed on a FACSCalibur device with CellQuest software (Becton Dickinson). A negative control (PBMCs alone) and a positive control (PBMCs stimulated with phytohemagglutinin) were included in each assay. The range of IFN‐γ production in the HIV‐1–seronegative control subjects ranged from 0.00% to 0.03% when cells were stimulated by the pools of overlapping peptides. Responses >0.03% above background were considered to indicate positivity. In the cohort of HIV‐1–positive subjects, the median background activity for both CD8<sup>+</sup> and CD4<sup>+</sup> cells without peptide pools was 0.02%. The range of background activity for CD8<sup>+</sup> T cells was 0.00%–0.03% (with a single outlier of 0.2%), and that for CD4<sup>+</sup> cells was 0.00%–0.09% (with a single outlier of 0.15%). For each subject, 100,000 events were collected. The total CD8<sup>+</sup> and total CD4<sup>+</sup> cell responses were obtained by subtracting the negative control from each pool and summing them.</p>
<p><bold><italic>Statistical analysis. </italic></bold>Statistical analysis was performed by use of the Mann‐Whitney <italic>U</italic> test and linear‐regression analysis. Correlations were assessed by use of Spearman’s rank correlation. Graphical presentation was performed by use of Prism software (version 4; GraphPad).</p></sec>
<sec id="S2">
<title>Results</title>
<p><bold><italic>Relative frequencies of HIV‐1–specific CD8</italic></bold><sup><bold><italic>+</italic></bold></sup><bold><italic>and CD4</italic></bold><sup><bold><italic>+</italic></bold></sup><bold><italic>cell responses in subjects chronically infected with clade C virus. </italic></bold>Previous studies have examined T cell responses to HIV‐1 clade C infection by use of the enzyme‐linked immunospot (ELISPOT) assay [<xref ref-type="bibr" rid="ref16">16</xref>, <xref ref-type="bibr" rid="ref19">19</xref>, <xref ref-type="bibr" rid="ref22">22</xref>], without differentiating the responses mediated by CD4<sup>+</sup> and CD8<sup>+</sup> cells. To assess and compare the relative magnitudes and frequencies of CD8<sup>+</sup> and CD4<sup>+</sup> cell responses to different viral proteins, the production of IFN‐γ was assessed by flow cytometry with an ICS assay.</p>
<p>Representative data for 1 subject are shown in <xref ref-type="fig" rid="Fig1">figure 1</xref>. Significant IFN‐γ production was detected in the CD8<sup>+</sup> T cell subset in all 65 subjects (median, 2.76%; range, 0.33%–27%). HIV‐1 Gag‐specific CD8<sup>+</sup> T cell responses were the most frequently detected (63/65 subjects; median, 0.75%; range, 0.04%–14.1%) (<xref ref-type="fig" rid="Fig2">figure 2<italic>A</italic></xref>). The pool of accessory and regulatory proteins (NTRVVV) and Pol pools were recognized at high frequency by CD8<sup>+</sup> T cells from the majority of subjects, with 95% of subjects recognizing each of these protein pools. The median magnitude of responses to these pools was quite similar to that for Gag (median for NTRVVV, 0.83%; median for Pol, 0.84%). The least frequently targeted protein was Env, with only 47 (72%) of 65 subjects having Env‐specific responses. The magnitude of the Env‐specific responses was almost always the lowest of all proteins (median, 0.17%; range, 0.04–1.55%); this was significantly lower than the response for each of the other 3 pools (<inline-formula>P<.0001</inline-formula>, Mann‐Whitney <italic>U</italic> test). These results indicate that, in persons chronically infected with clade C virus, CD8<sup>+</sup> T cell responses are broadly directed against multiple proteins but less frequently so against Env.</p>
<p>The magnitude of HIV‐specific CD4<sup>+</sup> cell responses was found to be lower than that of CD8<sup>+</sup> T cell responses (<xref ref-type="fig" rid="Fig2">figure 2<italic>B</italic></xref>). Fifty‐nine of 65 subjects had detectable HIV‐specific CD4<sup>+</sup> responses (median, 0.24%; range, 0.04%–1.42%). The average percentage of the CD4<sup>+</sup> cell compartment directed against HIV was 11‐fold less than the percentage of the CD8<sup>+</sup> T cell compartment directed against HIV. In contrast to the widely distributed CD8<sup>+</sup> T cell responses, the CD4<sup>+</sup> cell responses directed against Gag were of a much larger magnitude than those directed against the other pools (<inline-formula>P<.001</inline-formula>, Mann‐Whitney <italic>U</italic> test). The CD4<sup>+</sup> Env‐specific T cell responses were detected least frequently, were of the smallest overall magnitude (median, 0.05%; range, 0.04%–0.13%), and were significantly lower than the CD4<sup>+</sup> Gag‐, NTRVVV‐, and Pol‐specific T cell responses (<inline-formula>P<.001</inline-formula>, Mann‐Whitney <italic>U</italic> test). Also, the absolute number of CD4<sup>+</sup> cells for a specific pool was significantly lower than the absolute number of CD8<sup>+</sup> T cells specific for that same pool (<inline-formula>P<.001</inline-formula>, Mann‐Whitney <italic>U</italic> test; data not shown). These results indicate that multiple HIV‐1 clade C proteins serve as targets for CD4<sup>+</sup> helper cells but that responses are predominantly directed toward Gag and that the magnitude of these responses is significantly smaller than that observed for CD8<sup>+</sup> T cell responses to the same antigens (<inline-formula>P<.001</inline-formula>, Mann‐Whitney <italic>U</italic> test).</p>
<p><bold><italic>Relationship between magnitudes of HIV‐1–specific CD4</italic></bold><sup><bold><italic>+</italic></bold></sup><bold><italic>and CD8</italic></bold><sup><bold><italic>+</italic></bold></sup><bold><italic>cell activity. </italic></bold>Having detected persistent CD4<sup>+</sup> and CD8<sup>+</sup> cell responses to HIV, we next evaluated the relationship between CD8<sup>+</sup> and CD4<sup>+</sup> cell activity in the cohort of 65 subjects. A significant positive correlation between the frequency of total HIV‐1–specific CD4<sup>+</sup> and CD8<sup>+</sup> cells was identified (<italic>P</italic> = .0008, <inline-formula>R=0.4</inline-formula>, Spearman rank correlation) (<xref ref-type="fig" rid="Fig3">figure 3<italic>A</italic></xref>). Analysis on the basis of individual peptide pools revealed positive correlations between CD8<sup>+</sup> and CD4<sup>+</sup> cell responses specific for NTRVVV (<inline-formula>P<.0001</inline-formula>, <inline-formula>R=0.47</inline-formula>), Pol (<inline-formula>P=.0013</inline-formula>, <italic>R</italic> = 0.39), and Env (<inline-formula>P=.02</inline-formula>, <inline-formula>R=0.28</inline-formula>) and a positive trend between the Gag‐specific CD4<sup>+</sup> and CD8<sup>+</sup> T cell responses (<inline-formula>P=.06</inline-formula>, <inline-formula>R=0.23</inline-formula>).</p>
<p>To assess the consistency of these findings across similar cohorts, we analyzed a second cohort of 138 therapy‐naive subjects for whom only the Gag‐specific CD4<sup>+</sup> and CD8<sup>+</sup> cell responses were assessed. A significant positive correlation between the HIV‐1 Gag‐specific CD8<sup>+</sup> and CD4<sup>+</sup> cell responses was found (<inline-formula>P<.0001</inline-formula>, <inline-formula>R=0.41</inline-formula>) (<xref ref-type="fig" rid="Fig3">figure 3<italic>B</italic></xref>). We also examined another cohort of 160 chronically infected men and nonpregnant women. Here, too, the frequency of IFN‐γ production from Gag‐specific CD8<sup>+</sup> and CD4<sup>+</sup> cells was correlated (<inline-formula>P=.02</inline-formula>; <inline-formula>R=0.19</inline-formula>) (<xref ref-type="fig" rid="Fig3">figure 3<italic>C</italic></xref>). For the 363 subjects, there was a strong correlation between the magnitude of IFN‐γ–producing CD8<sup>+</sup> and CD4<sup>+</sup> cell responses (<inline-formula>P<.0001</inline-formula>; <inline-formula>R=0.34</inline-formula>) (<xref ref-type="fig" rid="Fig3">figure 3<italic>D</italic></xref>), which indicates that HIV‐specific CD4<sup>+</sup> and CD8<sup>+</sup> cell responses are linked; however, within individual cohorts, there exists substantial variation that affects the significance and strength of the associations observed (<inline-formula>R=0.4</inline-formula>, <inline-formula>R=0.41</inline-formula>, and <inline-formula>R=0.19</inline-formula>, respectively).</p>
<p><bold><italic>Relationship between magnitude of T cell responses and viral load. </italic></bold>We next assessed whether there was any relationship between the magnitude of HIV‐specific T cell responses and viral load. In the cohort of 65 patients, there was no association between total CD8<sup>+</sup> T cell responses and viral load (<xref ref-type="fig" rid="Fig4">figure 4<italic>A</italic></xref>). Although there was a trend toward a lower viral load in persons with higher magnitudes of Gag‐specific responses (<xref ref-type="fig" rid="Fig4">figure 4<italic>B</italic></xref>), this was not significant in the other 2 cohorts or when all 3 cohorts were combined (data not shown). The total and Gag‐specific CD4<sup>+</sup> cell responses showed no correlation with plasma viral load (figure <xref ref-type="fig" rid="Fig4">4<italic>C</italic></xref> and <xref ref-type="fig" rid="Fig4">4<italic>D</italic></xref>). A similar analysis of responses to other viral proteins revealed a similar lack of correlation between magnitude of CD8<sup>+</sup> or CD4<sup>+</sup> cell responses and viral load.</p>
<p>Because the presence of antigen‐specific CD4<sup>+</sup> cells appears to be critical for maintenance of effective immunity [<xref ref-type="bibr" rid="ref23">23</xref><xref ref-type="bibr" rid="ref24"></xref><xref ref-type="bibr" rid="ref25"></xref>–<xref ref-type="bibr" rid="ref26">26</xref>], we also examined whether the ratio of CD4<sup>+</sup>&rcolon;CD8<sup>+</sup> cells in terms of absolute number would correlate with viral load. The median number of HIV‐specific CD8<sup>+</sup> T cells was 11 times greater than that of HIV‐specific CD4<sup>+</sup> cells, but the ratio of antigen‐specific CD4<sup>+</sup> cells&rcolon;antigen‐specific CD8<sup>+</sup> T cells showed no association with viral load (data not shown). This implies that, in chronic HIV‐1 infection, there may be no threshold ratio of numbers of CD4<sup>+</sup>&rcolon;CD8<sup>+</sup> cells associated with viral containment, at least as measured by IFN‐γ production.</p>
<p><bold><italic>Relative targeting of individual proteins by CD8</italic></bold><sup><bold><italic>+</italic></bold></sup><bold><italic>and CD4</italic></bold><sup><bold><italic>+</italic></bold></sup><bold><italic>cells within individual subjects. </italic></bold>To further define the HIV‐specific cellular immune responses within individual subjects, we assessed the relative contribution of responses to each of the pools and compared this with the overall virus‐specific CD8<sup>+</sup> and CD4<sup>+</sup> cell responses (<xref ref-type="fig" rid="Fig5">figure 5</xref>). In terms of HIV‐specific CD4<sup>+</sup> cell responses, 56 of 59 CD4<sup>+</sup> cell responders displayed Gag‐specific responses; in the majority of these (79%), Gag was the major target antigen, and in 4 subjects it was the only target. By contrast, Gag was the dominant CD8<sup>+</sup> T cell target in the minority of persons (40%), and it was never the exclusive target. In each individual, the CD8<sup>+</sup> and CD4<sup>+</sup> Env‐specific responses made a significantly smaller contribution to the total CD8<sup>+</sup> and total CD4<sup>+</sup> cell responses than responses by the other protein pools (<inline-formula>P<.01</inline-formula>, Mann‐Whitney <italic>U</italic> test).</p>
<p><bold><italic>Relationship between dominant targeting of individual proteins and viral load. </italic></bold>We next examined whether the preferential targeting of specific regions of the virus might be associated with the control of viral load in the cohort of 65 persons. Although Nef is targeted more often during early clade C infection, the preferential targeting of Gag has been associated with significantly lower viral loads in studies that have used PBMCs in IFN‐γ ELISPOT assays [<xref ref-type="bibr" rid="ref19">19</xref>]. In the present study, using flow cytometry to differentiate CD4<sup>+</sup> and CD8<sup>+</sup> cell populations in PBMCs, we found that Gag was the most frequent dominant response for both CD8<sup>+</sup> and CD4<sup>+</sup> cells, followed by Pol and then NTRVVV, with no patient having a dominant Env T cell response. There were no significant differences between the median viral loads of the dominant CD4<sup>+</sup> Gag, Pol, and NTRVVV responders. However, subjects with a dominant CD8<sup>+</sup> Gag response had a significantly lower viral load than did subjects with a dominant CD8<sup>+</sup> response to non‐Gag proteins (median viral loads, 6055 and 31,100 copies/mL, respectively; <inline-formula>P=.007</inline-formula>, Mann‐Whitney <italic>U</italic> test) (<xref ref-type="fig" rid="Fig6">figure 6</xref>). These data indicate that, during chronic HIV‐1 infection, although there is no association between the magnitude of Gag‐specific CD8<sup>+</sup> T cell responses and viral load, there is an association between the preferential targeting of Gag by CD8<sup>+</sup> T cells and viral control.</p></sec>
<sec id="S3">
<title>Discussion</title>
<p>The few immunologic studies of HIV‐1 clade C infection published thus far have characterized T cell responses by use of IFN‐γ ELISPOT assay with whole PBMCs, which does not permit differentiation between CD8<sup>+</sup> and CD4<sup>+</sup> cell responses. In the present study, we used an IFN‐γ ICS assay, which allows the simultaneous quantitation of both CD4<sup>+</sup> and CD8<sup>+</sup> cell responses. Our results show that IFN‐γ CD8<sup>+</sup> and CD4<sup>+</sup> cell responses persist in the majority of persons with clade C infection and that there is a significant positive association between HIV‐1–specific CD8<sup>+</sup> and CD4<sup>+</sup> cell responses, although the magnitude of antigen‐specific CD8<sup>+</sup> T cell responses is substantially higher than that of CD4<sup>+</sup> cell responses. There is, however, no threshold ratio of virus‐specific CD4<sup>+</sup>&rcolon;CD8<sup>+</sup> cells that is associated with enhanced viral control, nor is there a correlation between the magnitude of these responses and viral load as measured by IFN‐γ production, which is consistent with the hypothesis that IFN‐γ production may be a poor indicator of antiviral T cell function. However, there was a significantly lower viral load in persons with CD8<sup>+</sup> T cells that preferentially target the HIV‐1 Gag protein, and this protein was also the major target for CD4<sup>+</sup> cells, which suggests its importance for vaccine development.</p>
<p>These data add to those from prior studies of HIV‐specific CD8<sup>+</sup> T cell responses in therapy‐naive persons with clade B [<xref ref-type="bibr" rid="ref27">27</xref><xref ref-type="bibr" rid="ref28"></xref>–<xref ref-type="bibr" rid="ref29">29</xref>] and clade C [<xref ref-type="bibr" rid="ref19">19</xref>, <xref ref-type="bibr" rid="ref22">22</xref>] infections, which showed a broad recognition of structural and regulatory proteins. In our study, all therapy‐naive subjects had detectable CD8<sup>+</sup> T cell responses directed against Gag and to at least 1 other region of the virus. Gag, Pol, and NTRVVV represented the dominant CD8<sup>+</sup> T cell target with roughly equal frequencies. In contrast, Gag was the dominant target for CD4<sup>+</sup> cell responses in almost 80% of persons. Preferential targeting of Gag by CD8<sup>+</sup> T cells, compared with the targeting of other proteins, was associated with a lower viral load, because Gag may tolerate less sequence diversity, given that it is the most highly conserved protein. This finding should be examined in additional cohorts to see whether the relationship holds. For both CD8<sup>+</sup> and CD4<sup>+</sup> cell responses, the Env pool of peptides elicited the smallest number and magnitude of responses. The greater variability of the Env region of HIV‐1 means that an assessment of Env‐specific immune responses with the consensus sequence that we used would be more likely to miss responses to autologous virus than would be the case for other, more‐conserved proteins.</p>
<p>These results differ in important dimensions from earlier studies of both clade B and C infections, particularly with respect to the relationship between HIV‐1–specific T cell responses and viral load. The existing literature on CD4<sup>+</sup> cell responses in HIV‐1 infection, which has been largely confined to clade B infection, has yielded conflicting results in terms of the relationship between these responses and the control of viral load [<xref ref-type="bibr" rid="ref5">5</xref>, <xref ref-type="bibr" rid="ref15">15</xref>, <xref ref-type="bibr" rid="ref27">27</xref>, <xref ref-type="bibr" rid="ref30">30</xref>]. This could be due to the very small numbers of subjects recruited for some of the studies and different assays being used to quantify CD4<sup>+</sup> cell function. We found no correlation between Gag‐specific CD8<sup>+</sup> or CD4<sup>+</sup> cell responses and viral load or between the threshold ratio of CD4<sup>+</sup>&rcolon;CD8<sup>+</sup> cells and viral load in the largest cohort (<inline-formula>n=351</inline-formula>) studied to date. However, our data corroborate and extend those of Masemola et al. [<xref ref-type="bibr" rid="ref18">18</xref>], who showed the preferential targeting of Gag to be associated with a lower viral load, in that our data further dissect the contribution of CD8<sup>+</sup> and CD4<sup>+</sup> cell responses and show that the preferential targeting of Gag by CD8<sup>+</sup> T cells is associated with enhanced control of viral load.</p>
<p>We have also observed the preservation of CD4<sup>+</sup> T cell responses to infection with clade C virus in persons who have not been exposed to therapy, as defined by IFN‐γ production by CD4<sup>+</sup> T cells. This corroborates studies of clade B infection that showed CD4<sup>+</sup> IFN‐γ production in a majority of chronically infected subjects, regardless of the stage of disease [<xref ref-type="bibr" rid="ref31">31</xref>]. We have conclusively shown that, in contrast to CD8<sup>+</sup> T cell responses, CD4<sup>+</sup> cell responses occur more frequently in response to the Gag proteins than in response to any of the other regions in the expressed clade C genome. The dominance of CD4<sup>+</sup> responses to the Gag pool of peptides is unlikely to be due to greater conservation of sequence alone, given that Pol is at least as well conserved and that it elicited similar CD8<sup>+</sup> responses yet fewer CD4<sup>+</sup> responses. The reasons for the smaller magnitude of CD4<sup>+</sup> cell responses, compared with that of CD8<sup>+</sup> responses, remains unclear.</p>
<p>It has been shown that HIV‐1–infected subjects who control infection are those who have CD4<sup>+</sup> proliferative responses and that IFN‐γ production is less able to predict viral control [<xref ref-type="bibr" rid="ref5">5</xref>, <xref ref-type="bibr" rid="ref15">15</xref>, <xref ref-type="bibr" rid="ref27">27</xref>, <xref ref-type="bibr" rid="ref31">31</xref><xref ref-type="bibr" rid="ref32"></xref>–<xref ref-type="bibr" rid="ref33">33</xref>]. More recently, interleukin (IL)–2 production by CD4<sup>+</sup> cells has been associated with the control of HIV‐1 replication [<xref ref-type="bibr" rid="ref33">33</xref><xref ref-type="bibr" rid="ref34"></xref>–<xref ref-type="bibr" rid="ref35">35</xref>]. The only study that has examined IL‐2–specific CD4<sup>+</sup> responses in clade C HIV‐1 infection was conducted in chronically infected children; those researchers found that the presence of IL‐2 in Env‐specific PBMCs was negatively correlated with viral load [<xref ref-type="bibr" rid="ref20">20</xref>]. The role of HIV‐1–specific CD4<sup>+</sup> cells producing IL‐2, as well as CD4<sup>+</sup> proliferative activity, in persons with chronic clade C infection remains to be investigated.</p>
<p>In summary, the present studies of antiretroviral therapy–naive subjects in Durban, South Africa, indicate a correlation between CD8<sup>+</sup> and CD4<sup>+</sup> cell IFN‐γ activity but much more narrowly focused CD4<sup>+</sup> responses than CD8<sup>+</sup> T cell responses. The lack of a strong association between the magnitude of CD8<sup>+</sup> or CD4<sup>+</sup> cell activity with viral load, as well as the lack of a threshold ratio between virus‐specific CD4<sup>+</sup> to CD8<sup>+</sup> cell responses for the control of viral load, indicates that additional factors beyond antigen‐specific IFN‐γ production are important for the relative immune containment of infection with clade C virus. One possibility suggested by our data is that the preferential targeting of Gag by CD8<sup>+</sup> T cells may be important for immune containment. This will need to be investigated further, and it may lead to better insights into the pathogenesis of HIV disease and provide a rationale for vaccine development.</p></sec>
</body>
<back>
<ack>
<title>Acknowledgments</title>
<p>We thank the subjects and staff at the Ekuphileni Cato Manor Antenatal Clinic, St. Mary’s Antenatal clinic, and the Sinikithemba Clinic at McCord Hospital (Durban, South Africa), for their cooperation.</p>
</ack>
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<sec sec-type="display-objects">
<title>Figures and Tables</title>
<fig id="Fig1" position="float">
<label>Figure 1. </label>
<caption>
<p>HIV‐specific CD8<sup>+</sup> and CD4<sup>+</sup> cell responses as detected by flow cytometry. <italic>Top,</italic> Dot plots of CD8<sup>+</sup> T cell responses to the negative control on the left and to a pool of Gag peptides on the right. <italic>Bottom,</italic> dot plots of the CD4<sup>+</sup> cell response to the negative control on the left and to the pool of Gag peptides on the right. This figure depicts the simultaneous detection of CD8<sup>+</sup> and CD4<sup>+</sup> cell responses in an individual subject. The response to the Gag pool of peptides displayed was calculated after the subtraction of background. APC, allophycocyanin; FITC, fluorescein isothiocyanate; IFN, interferon; PE, phycoerythrin.</p>
</caption>
<graphic mimetype="image" xlink:href="192-9-1588-fig001.tif"></graphic>
</fig>
<fig id="Fig2" position="float">
<label>Figure 2. </label>
<caption>
<p>Relative magnitudes of HIV‐1–specific CD8<sup>+</sup> and CD4<sup>+</sup> cell responses to different viral proteins. The magnitude of the CD8<sup>+</sup> and CD4<sup>+</sup> cell responses to each of the peptide pools is shown. There were no significant differences between the magnitudes of the CD8<sup>+</sup> Gag‐, Nef/Tat/Rev/Vpr/Vpu/Vif (NTRVVV)–, or Pol‐specific T cell responses <italic>(A)</italic>. The magnitude of the HIV‐1 Env‐specific CD8<sup>+</sup> T cell response was significantly lower than the CD8<sup>+</sup> T cell responses for each of the other 3 proteins. The magnitude of the HIV‐1 Gag‐specific CD4<sup>+</sup> cell response was significantly greater than the CD4<sup>+</sup> cell responses for the other 3 proteins <italic>(B)</italic>. The magnitude of the Env‐specific CD4<sup>+</sup> cell responses was significantly lower than the magnitudes of the NTRVVV‐ and Pol‐specific CD4<sup>+</sup> cell responses.</p>
</caption>
<graphic mimetype="image" xlink:href="192-9-1588-fig002.tif"></graphic>
</fig>
<fig id="Fig3" position="float">
<label>Figure 3. </label>
<caption>
<p>Positive association between HIV‐1 CD8<sup>+</sup> and CD4<sup>+</sup> cell responses. <italic>A,</italic> Positive correlation between the total HIV‐1–specific CD8<sup>+</sup> and CD4<sup>+</sup> cell responses in a cohort of 65 subjects. <italic>B,</italic> Positive association between HIV‐1 Gag‐specific CD8<sup>+</sup> and CD4<sup>+</sup> cell responses in a second cohort of 138 pregnant subjects. <italic>C,</italic> Positive relationship between Gag‐specific CD8<sup>+</sup> and CD4<sup>+</sup> cell responses in a separate cohort of 160 subjects. This latter cohort was composed of chronically infected men and nonpregnant women and shows that the findings of the study can be extrapolated to the general population. <italic>D,</italic> Positive correlation between CD8<sup>+</sup> and CD4<sup>+</sup> interferon‐γ production in all 363 patients.</p>
</caption>
<graphic mimetype="image" xlink:href="192-9-1588-fig003.tif"></graphic>
</fig>
<fig id="Fig4" position="float">
<label>Figure 4. </label>
<caption>
<p>Relationship between viral load (in copies/mL) and magnitude of HIV‐1–specific T cell responses (<inline-formula>n=65</inline-formula>). There was no correlation between the total CD8<sup>+</sup> T cell response and viral load <italic>(A)</italic>. Although the Gag‐specific CD8<sup>+</sup> T cell responses showed a negative trend relationship to viral load in the initial cohort <italic>(B),</italic> this was not the case for the other 2 cohorts or when data from all 3 cohorts were combined (data not shown), and CD8<sup>+</sup> T cell responses from the remaining 3 peptide pools showed no association with viral load (data not shown). There were no significant associations between total or Gag‐specific CD4<sup>+</sup> cell responses and viral load <italic>(C</italic> and <italic>D)</italic> or between CD4<sup>+</sup> cell responses specific for any of the other peptide pools and viral load (data not shown) .</p>
</caption>
<graphic mimetype="image" xlink:href="192-9-1588-fig004.tif"></graphic>
</fig>
<fig id="Fig5" position="float">
<label>Figure 5. </label>
<caption>
<p>Contribution of each protein pool to the total CD8<sup>+</sup> <italic>(top)</italic> and total CD4<sup>+</sup> <italic>(bottom)</italic> cell responses, in each subject. Subjects are numbered from 1 to 65. There was no correlation between the dominant CD8<sup>+</sup> T cell target and the dominant CD4<sup>+</sup> cell target. “NTRVVV” denotes Nef, Tat, Rev, Vpr, Vpu, and Vif.</p>
</caption>
<graphic mimetype="image" xlink:href="192-9-1588-fig005.tif"></graphic>
</fig>
<fig id="Fig6" position="float">
<label>Figure 6. </label>
<caption>
<p>Subjects with a dominant Gag‐specific CD8<sup>+</sup> T cell response and significantly lower median viral load vs. subjects with a dominant CD8<sup>+</sup> T cell response to non‐Gag proteins (Other). The non‐Gag proteins that were dominantly targeted included Pol and Nef/Tat/Rev/Vpr/Vpu/Vif regions of HIV‐1; there were no subjects with a dominant Env‐specific CD8<sup>+</sup> T cell response.</p>
</caption>
<graphic mimetype="image" xlink:href="192-9-1588-fig006.tif"></graphic>
</fig></sec>
<fn-group>
<fn id="fn1">
<p>Presented in part: 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, February 2004 (abstract A‐89).</p>
<p>Potential conflicts of interest: none reported.</p>
<p>Financial support: National Institutes of Health (grant RO1 AI46995‐01A1 [to P.G.] and grants RO1‐AI‐46366, RO1‐AI‐49120, RO1‐AI‐52056, and P51 RR001676‐43 and contract NO1 AI 15442 [to B.W.]); Doris Duke Charitable Foundation (to D.R. and B.W.). Howard Hughes Medical Institute; Harvard Medical School Center for AIDS Research; Wellcome Trust (to P.G.). P.G. is an Elizabeth Glaser Scientist.</p></fn>
<fn id="fn2">
<p>Present affiliations: Human Sciences Research Council, Cape Town, South Africa (N.C.M.); Columbia University, New York, New York (J.D.H.); The Peter Medwar Building for Pathogen Research, Oxford, United Kingdom (I.H.).</p></fn>
</fn-group>
</back>
</article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Differential Immunogenicity of HIV‐1 Clade C Proteins in Eliciting CD8+ and CD4+ Cell Responses</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Differential Immunogenicity of HIV‐1 Clade C Proteins in Eliciting CD8+ and CD4+ Cell Responses</title></titleInfo><name type="personal" displayLabel="corresp"><namePart type="given">Danni </namePart><namePart type="family">Ramduth</namePart><affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</affiliation><affiliation>E-mail: ramduthd1@ukzn.ac.za</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Polan </namePart><namePart type="family">Chetty</namePart><affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Nolwandle Cyloria </namePart><namePart type="family">Mngquandaniso</namePart><affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Nonhlanhla </namePart><namePart type="family">Nene</namePart><affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jason Davis </namePart><namePart type="family">Harlow</namePart><affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Isobella </namePart><namePart type="family">Honeyborne</namePart><affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Nelisiwe </namePart><namePart type="family">Ntumba</namePart><affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sharika </namePart><namePart type="family">Gappoo</namePart><affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Chiara </namePart><namePart type="family">Henry</namePart><affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Prakash </namePart><namePart type="family">Jeena</namePart><affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Marylyn Martina </namePart><namePart type="family">Addo</namePart><affiliation>Partners AIDS Research Center and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Marcus </namePart><namePart type="family">Altfeld</namePart><affiliation>Partners AIDS Research Center and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christian </namePart><namePart type="family">Brander</namePart><affiliation>Partners AIDS Research Center and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Cheryl </namePart><namePart type="family">Day</namePart><affiliation>Peter Medwar Building for Pathogen Research, Oxford University, Oxford, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hoosen </namePart><namePart type="family">Coovadia</namePart><affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Photini </namePart><namePart type="family">Kiepiela</namePart><affiliation>HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu‐Natal, Durban, South Africa;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Philip </namePart><namePart type="family">Goulder</namePart><affiliation>Partners AIDS Research Center and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;</affiliation><affiliation>Peter Medwar Building for Pathogen Research, Oxford University, Oxford, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Bruce </namePart><namePart type="family">Walker</namePart><affiliation>Partners AIDS Research Center and Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>The University of Chicago Press</publisher><dateIssued encoding="w3cdtf">2005-11-01</dateIssued><dateCreated encoding="w3cdtf">2005-06-01</dateCreated><copyrightDate encoding="w3cdtf">2005</copyrightDate></originInfo><abstract>Background. The relative immunogenicity of human immunodeficiency virus type 1 (HIV‐1) proteins for CD8+ and CD4+ cell responses has not been defined. Methods. HIV‐1–specific T cell responses were evaluated in 65 chronically HIV‐1–infected untreated subjects by interferon‐γ flow cytometry with peptides spanning the clade C consensus sequence. Results. The magnitude of HIV‐1–specific CD8+ T cell responses correlated significantly with CD4+ cell responses, but the percentage of CD8+ T cells directed against HIV‐1 (median, 2.76%) was always greater than that of CD4+ cells (median, 0.24%). Although CD8+ T cell responses were equally distributed among Gag, Pol, and the regulatory and accessory proteins, Gag was the dominant target for CD4+ cell responses. There was no consistent relationship between virus‐specific CD8+ or CD4+ cell response and viral load. However, the median viral load in subjects in whom Gag was the dominant CD8+ T cell target was significantly lower than that in subjects in whom non‐Gag proteins were the main target (P=.007). Conclusions. Gag‐specific responses dominate the CD4+ T cell response to HIV, whereas CD8+ T cell responses are broadly distributed, which indicates differential immunogenicity of these cells against HIV‐1. 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