{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T15:07:40Z","timestamp":1791990460519,"version":"4.4.0"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2012,4,1]],"date-time":"2012-04-01T00:00:00Z","timestamp":1333238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>HIV\/SIV infections induce chronic immune activation with remodeling of lymphoid architecture and hypergammaglobulinemia, although the mechanisms leading to such symptoms remain to be fully elucidated. Moreover, lymph nodes have been highlighted as a predilection site for SIV escape in vivo. Following 20 rhesus macaques infected with SIVmac239 as they progress from pre-infection to acute and chronic infection, we document for the first time, to our knowledge, the local dynamics of T follicular helper (TFH) cells and B cells in situ. Progression of SIV infection was accompanied by increased numbers of well-delineated follicles containing germinal centers (GCs) and TFH cells with a progressive increase in the density of programmed death-1 (PD-1) expression in lymph nodes. The rise in PD-1+ TFH cells was followed by a substantial accumulation of Ki67+ B cells within GCs. However, unlike in blood, major increases in the frequency of CD27+ memory B cells were observed in lymph nodes, indicating increased turnover of these cells, correlated with increases in total and SIV specific Ab levels. Of importance, compared with T cell zones, GCs seemed to exclude CD8+ T cells while harboring increasing numbers of CD4+ T cells, many of which are positive for SIVgag, providing an environment particularly beneficial for virus replication and reservoirs. Our data highlight for the first time, to our knowledge, important spatial interactions of GC cell subsets during SIV infection, the capacity of lymphoid tissues to maintain stable relative levels of circulating B cell subsets, and a potential mechanism for viral reservoirs within GCs during SIV infection.<\/jats:p>","DOI":"10.4049\/jimmunol.1103138","type":"journal-article","created":{"date-parts":[[2012,3,5]],"date-time":"2012-03-05T15:05:47Z","timestamp":1330959947000},"page":"3247-3256","source":"Crossref","is-referenced-by-count":149,"title":["Spatial Alterations between CD4+ T Follicular Helper, B, and CD8+ T Cells during Simian Immunodeficiency Virus Infection: T\/B Cell Homeostasis, Activation, and Potential Mechanism for Viral Escape"],"prefix":"10.1093","volume":"188","author":[{"given":"Jung Joo","family":"Hong","sequence":"first","affiliation":[{"name":"Division of Pathology, Yerkes National Primate Research Center , Atlanta, GA 30329"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Praveen K","family":"Amancha","sequence":"additional","affiliation":[{"name":"Division of Pathology, Yerkes National Primate Research Center , Atlanta, GA 30329"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Rogers","sequence":"additional","affiliation":[{"name":"Division of Pathology, Yerkes National Primate Research Center , Atlanta, GA 30329"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aftab A","family":"Ansari","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, Emory University School of Medicine , Atlanta, GA 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francois","family":"Villinger","sequence":"additional","affiliation":[{"name":"Division of Pathology, Yerkes National Primate Research Center , Atlanta, GA 30329"},{"name":"Department of Pathology & Laboratory Medicine, Emory University School of Medicine , Atlanta, GA 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,4,1]]},"reference":[{"key":"2025032410004898400_r1","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.immuni.2007.07.009","article-title":"Germinal-center organization and cellular dynamics","volume":"27","author":"Allen","year":"2007","journal-title":"Immunity"},{"key":"2025032410004898400_r2","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1146\/annurev.immunol.22.012703.104527","article-title":"Immunological memory to viral infections","volume":"22","author":"Welsh","year":"2004","journal-title":"Annu. Rev. Immunol."},{"key":"2025032410004898400_r3","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.it.2010.07.001","article-title":"The elusive identity of T follicular helper cells","volume":"31","author":"Yu","year":"2010","journal-title":"Trends Immunol."},{"key":"2025032410004898400_r4","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/1471-2172-12-53","article-title":"Phenotype, effector function, and tissue localization of PD-1-expressing human follicular helper T cell subsets","volume":"12","author":"Wang","year":"2011","journal-title":"BMC Immunol."},{"key":"2025032410004898400_r5","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.immuni.2008.06.001","article-title":"A fundamental role for interleukin-21 in the generation of T follicular helper cells","volume":"29","author":"Vogelzang","year":"2008","journal-title":"Immunity"},{"key":"2025032410004898400_r6","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/nri727","article-title":"The B7-CD28 superfamily","volume":"2","author":"Sharpe","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"2025032410004898400_r7","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1146\/annurev.immunol.23.021704.115611","article-title":"The B7 family revisited","volume":"23","author":"Greenwald","year":"2005","journal-title":"Annu. Rev. Immunol."},{"key":"2025032410004898400_r8","doi-asserted-by":"crossref","first-page":"5099","DOI":"10.4049\/jimmunol.179.8.5099","article-title":"Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation","volume":"179","author":"Haynes","year":"2007","journal-title":"J. Immunol."},{"key":"2025032410004898400_r9","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.3324\/haematol.10864","article-title":"Expression of two markers of germinal center T cells (SAP and PD-1) in angioimmunoblastic T-cell lymphoma","volume":"92","author":"Roncador","year":"2007","journal-title":"Haematologica"},{"key":"2025032410004898400_r10","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1038\/377740a0","article-title":"Follicular dendritic cells and human immunodeficiency virus infectivity","volume":"377","author":"Heath","year":"1995","journal-title":"Nature"},{"key":"2025032410004898400_r11","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1097\/00002030-199707000-00003","article-title":"Germinal centre CD4+ T cells are an important site of HIV replication in vivo","volume":"11","author":"Hufert","year":"1997","journal-title":"AIDS"},{"key":"2025032410004898400_r12","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/S1044-5323(02)00060-X","article-title":"Follicular dendritic cell contributions to HIV pathogenesis","volume":"14","author":"Burton","year":"2002","journal-title":"Semin. Immunol."},{"key":"2025032410004898400_r13","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1128\/JVI.01652-08","article-title":"Follicular dendritic cells and human immunodeficiency virus type 1 transcription in CD4+ T cells","volume":"83","author":"Thacker","year":"2009","journal-title":"J. Virol."},{"key":"2025032410004898400_r14","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1126\/science.292.5514.69","article-title":"Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA\/MVA vaccine","volume":"292","author":"Amara","year":"2001","journal-title":"Science"},{"key":"2025032410004898400_r15","doi-asserted-by":"crossref","first-page":"6798","DOI":"10.4049\/jimmunol.180.10.6798","article-title":"Early resolution of acute immune activation and induction of PD-1 in SIV-infected sooty mangabeys distinguishes nonpathogenic from pathogenic infection in rhesus macaques","volume":"180","author":"Estes","year":"2008","journal-title":"J. Immunol."},{"key":"2025032410004898400_r16","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1099\/0022-1317-71-1-247","article-title":"Characterization of monoclonal antibodies that distinguish simian immunodeficiency virus isolates from each other and from human immunodeficiency virus types 1 and 2","volume":"71","author":"Sutjipto","year":"1990","journal-title":"J. Gen. Virol."},{"key":"2025032410004898400_r17","doi-asserted-by":"crossref","first-page":"9217","DOI":"10.1128\/JVI.79.14.9217-9227.2005","article-title":"Propagation and dissemination of infection after vaginal transmission of simian immunodeficiency virus","volume":"79","author":"Miller","year":"2005","journal-title":"J. Virol."},{"key":"2025032410004898400_r18","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/ni1316","article-title":"HIV disease: fallout from a mucosal catastrophe?","volume":"7","author":"Brenchley","year":"2006","journal-title":"Nat. Immunol."},{"key":"2025032410004898400_r19","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/nm1380","article-title":"Pathogenesis of HIV infection: what the virus spares is as important as what it destroys","volume":"12","author":"Grossman","year":"2006","journal-title":"Nat. Med."},{"key":"2025032410004898400_r20","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/nri2524","article-title":"B cells in HIV infection and disease","volume":"9","author":"Moir","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"2025032410004898400_r21","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1084\/jem.192.11.1553","article-title":"CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function","volume":"192","author":"Schaerli","year":"2000","journal-title":"J. Exp. Med."},{"key":"2025032410004898400_r22","doi-asserted-by":"crossref","first-page":"3352","DOI":"10.1002\/eji.200636746","article-title":"CXCR5+ CCR7- CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles","volume":"37","author":"Quigley","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"2025032410004898400_r23","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1084\/jem.192.11.1545","article-title":"Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production","volume":"192","author":"Breitfeld","year":"2000","journal-title":"J. Exp. Med."},{"key":"2025032410004898400_r24","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1084\/jem.20072683","article-title":"Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals","volume":"205","author":"Moir","year":"2008","journal-title":"J. Exp. Med."},{"key":"2025032410004898400_r25","doi-asserted-by":"crossref","first-page":"3878","DOI":"10.1172\/JCI43271","article-title":"Acute depletion of activated memory B cells involves the PD-1 pathway in rapidly progressing SIV-infected macaques","volume":"120","author":"Titanji","year":"2010","journal-title":"J. Clin. Invest."},{"key":"2025032410004898400_r26","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1002\/(SICI)1097-0320(19971201)29:4<351::AID-CYTO12>3.0.CO;2-T","article-title":"Lymphocyte subsets and expression of differentiation markers in blood and lymphoid organs of rhesus monkeys","volume":"29","author":"Sopper","year":"1997","journal-title":"Cytometry"},{"key":"2025032410004898400_r27","doi-asserted-by":"crossref","first-page":"e1002048","DOI":"10.1371\/journal.ppat.1002048","article-title":"Viral CTL escape mutants are generated in lymph nodes and subsequently become fixed in plasma and rectal mucosa during acute SIV infection of macaques","volume":"7","author":"Vanderford","year":"2011","journal-title":"PLoS Pathog."},{"key":"2025032410004898400_r28","first-page":"373","article-title":"Cellular localization of simian immunodeficiency virus in lymphoid tissues. I. Immunohistochemistry and electron microscopy","volume":"134","author":"Ringler","year":"1989","journal-title":"Am. J. Pathol."},{"key":"2025032410004898400_r29","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1038\/nature05115","article-title":"PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression","volume":"443","author":"Day","year":"2006","journal-title":"Nature"},{"key":"2025032410004898400_r30","doi-asserted-by":"crossref","first-page":"1979","DOI":"10.4049\/jimmunol.179.3.1979","article-title":"Programmed death 1 expression on HIV-specific CD4+ T cells is driven by viral replication and associated with T cell dysfunction","volume":"179","author":"D\u2019Souza","year":"2007","journal-title":"J. Immunol."},{"key":"2025032410004898400_r31","doi-asserted-by":"crossref","first-page":"7340","DOI":"10.4049\/jimmunol.1001642","article-title":"Increased B7-H1 expression on dendritic cells correlates with programmed death 1 expression on T cells in simian immunodeficiency virus-infected macaques and may contribute to T cell dysfunction and disease progression","volume":"185","author":"Xu","year":"2010","journal-title":"J. Immunol."},{"key":"2025032410004898400_r32","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1111\/j.1365-2567.2007.02766.x","article-title":"Soluble PD-1 rescues the proliferative response of simian immunodeficiency virus-specific CD4 and CD8 T cells during chronic infection","volume":"124","author":"Onlamoon","year":"2008","journal-title":"Immunology"},{"key":"2025032410004898400_r33","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nature04444","article-title":"Restoring function in exhausted CD8 T cells during chronic viral infection","volume":"439","author":"Barber","year":"2006","journal-title":"Nature"},{"key":"2025032410004898400_r34","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1189\/jlb.0610327","article-title":"Expression of PD-L1 and PD-L2 on human macrophages is up-regulated by HIV-1 and differentially modulated by IL-10","volume":"89","author":"Rodr\u00edguez-Garc\u00eda","year":"2011","journal-title":"J. Leukoc. Biol."},{"key":"2025032410004898400_r35","doi-asserted-by":"crossref","first-page":"3311","DOI":"10.1182\/blood-2010-02-271981","article-title":"Alternatively activated macrophages inhibit T-cell proliferation by Stat6-dependent expression of PD-L2","volume":"116","author":"Huber","year":"2010","journal-title":"Blood"},{"key":"2025032410004898400_r36","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1146\/annurev-immunol-031210-101400","article-title":"Follicular helper CD4 T cells (TFH)","volume":"29","author":"Crotty","year":"2011","journal-title":"Annu. Rev. Immunol."},{"key":"2025032410004898400_r37","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1182\/blood-2005-11-013383","article-title":"Loss of memory B cells impairs maintenance of long-term serologic memory during HIV-1 infection","volume":"108","author":"Titanji","year":"2006","journal-title":"Blood"},{"key":"2025032410004898400_r38","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1126\/science.280.5362.427","article-title":"Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection","volume":"280","author":"Veazey","year":"1998","journal-title":"Science"},{"key":"2025032410004898400_r39","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1084\/jem.20040874","article-title":"CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract","volume":"200","author":"Brenchley","year":"2004","journal-title":"J. Exp. Med."},{"key":"2025032410004898400_r40","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1038\/35876","article-title":"A B-cell-homing chemokine made in lymphoid follicles activates Burkitt\u2019s lymphoma receptor-1","volume":"391","author":"Gunn","year":"1998","journal-title":"Nature"},{"key":"2025032410004898400_r41","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1084\/jem.187.4.655","article-title":"B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1\/CXCR5","volume":"187","author":"Legler","year":"1998","journal-title":"J. Exp. Med."},{"key":"2025032410004898400_r42","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1038\/nri1222","article-title":"Homing and cellular traffic in lymph nodes","volume":"3","author":"von Andrian","year":"2003","journal-title":"Nat. Rev. Immunol."},{"key":"2025032410004898400_r43","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/ni.1877","article-title":"PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells","volume":"11","author":"Good-Jacobson","year":"2010","journal-title":"Nat. Immunol."},{"key":"2025032410004898400_r44","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1111\/j.1600-0684.1997.tb00050.x","article-title":"Immune stimulation may contribute to enhanced progression of SIV induced disease in rhesus macaques","volume":"26","author":"Folks","year":"1997","journal-title":"J. Med. Primatol."},{"key":"2025032410004898400_r45","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/icb.2009.64","article-title":"Early commitment of na\u00efve human CD4(+) T cells to the T follicular helper (T(FH)) cell lineage is induced by IL-12","volume":"87","author":"Ma","year":"2009","journal-title":"Immunol. Cell Biol."},{"key":"2025032410004898400_r46","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.immuni.2008.05.009","article-title":"Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages","volume":"29","author":"Nurieva","year":"2008","journal-title":"Immunity"},{"key":"2025032410004898400_r47","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1126\/science.1077002","article-title":"A critical role for IL-21 in regulating immunoglobulin production","volume":"298","author":"Ozaki","year":"2002","journal-title":"Science"},{"key":"2025032410004898400_r48","doi-asserted-by":"crossref","first-page":"5361","DOI":"10.4049\/jimmunol.173.9.5361","article-title":"Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6","volume":"173","author":"Ozaki","year":"2004","journal-title":"J. Immunol."},{"key":"2025032410004898400_r49","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1126\/science.274.5289.985","article-title":"Quantitative image analysis of HIV-1 infection in lymphoid tissue","volume":"274","author":"Haase","year":"1996","journal-title":"Science"},{"key":"2025032410004898400_r50","doi-asserted-by":"crossref","first-page":"5548","DOI":"10.1128\/JVI.00124-08","article-title":"Characterization of the follicular dendritic cell reservoir of human immunodeficiency virus type 1","volume":"82","author":"Keele","year":"2008","journal-title":"J. Virol."},{"key":"2025032410004898400_r51","doi-asserted-by":"crossref","first-page":"690","DOI":"10.4049\/jimmunol.166.1.690","article-title":"Persistence of infectious HIV on follicular dendritic cells","volume":"166","author":"Smith","year":"2001","journal-title":"J. Immunol."},{"key":"2025032410004898400_r52","doi-asserted-by":"crossref","first-page":"e23515","DOI":"10.1371\/journal.pone.0023515","article-title":"GagCM9-specific CD8+ T cells expressing limited public TCR clonotypes do not suppress SIV replication in vivo","volume":"6","author":"Vojnov","year":"2011","journal-title":"PLoS ONE"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/188\/7\/3247\/62483037\/1103138.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/188\/7\/3247\/62483037\/1103138.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T15:37:58Z","timestamp":1743089878000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/188\/7\/3247\/7981492"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,4,1]]},"references-count":52,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2012,4,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1103138","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.14266004.15778128","asserted-by":"object"}]},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2012,4]]},"published":{"date-parts":[[2012,4,1]]}}}