{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T19:06:38Z","timestamp":1774119998396,"version":"3.50.1"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2015,2,1]],"date-time":"2015-02-01T00:00:00Z","timestamp":1422748800000},"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":[[2015,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Lymphocytic alveolitis in HIV-1\u2013infected individuals is associated with multiple pulmonary complications and a poor prognosis. Although lymphocytic alveolitis has been associated with viremia and an increased number of CD8+ T cells in the lung, its exact cause is unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To determine if HIV-1\u2013specific T cells are associated with lymphocytic alveolitis in HIV-1\u2013infected individuals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using blood and bronchoalveolar lavage (BAL) cells from normal control subjects and untreated HIV-1\u2013infected individuals, we examined the frequency and functional capacity of HIV-1\u2013specific T cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>We found that HIV-1\u2013specific T cells were significantly elevated in the BAL compared with blood of HIV-1\u2013infected individuals and strongly correlated with T-cell alveolitis. Expression of Ki67, a marker of in vivo proliferation, was significantly reduced on HIV-1\u2013specific T cells in BAL compared with blood, suggesting a diminished proliferative capacity. In addition, HIV-1\u2013specific CD4+ and CD8+ T cells in BAL had higher expression of programmed death 1 (PD-1) and lower cytotoxic T-lymphocyte antigen 4 (CTLA-4) expression than those in the blood. A strong correlation between PD-1, but not CTLA-4, and HIV-1\u2013specific T-cell proliferation was seen, and blockade of the PD-1\/PD-L1 pathway augmented HIV-1\u2013specific T-cell proliferation, suggesting that the PD-1 pathway was the main cause of reduced proliferation in the lung.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings suggest that alveolitis associated with HIV-1 infection is caused by the recruitment of HIV-1\u2013specific CD4+ and CD8+ T cells to the lung. These antigen-specific T cells display an impaired proliferative capacity that is caused by increased expression of PD-1.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201408-1521oc","type":"journal-article","created":{"date-parts":[[2014,12,23]],"date-time":"2014-12-23T17:41:33Z","timestamp":1419356493000},"page":"464-473","source":"Crossref","is-referenced-by-count":50,"title":["Lymphocytic Alveolitis Is Associated with the Accumulation of Functionally Impaired HIV-Specific T Cells in the Lung of Antiretroviral Therapy\u2013Naive Subjects"],"prefix":"10.1093","volume":"191","author":[{"given":"C. Preston","family":"Neff","sequence":"first","affiliation":[{"name":"Department of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer L.","family":"Chain","sequence":"additional","affiliation":[{"name":"Department of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha","family":"MaWhinney","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Informatics, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allison K.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Derek J.","family":"Linderman","sequence":"additional","affiliation":[{"name":"Department of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia C.","family":"Flores","sequence":"additional","affiliation":[{"name":"Department of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas B.","family":"Campbell","sequence":"additional","affiliation":[{"name":"Department of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brent E.","family":"Palmer","sequence":"additional","affiliation":[{"name":"Department of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew P.","family":"Fontenot","sequence":"additional","affiliation":[{"name":"Department of Medicine"},{"name":"Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, Colorado"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2015,2,15]]},"reference":[{"key":"2026032100244757600_bib1","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1007\/s11904-012-0140-x","article-title":"Pathogenesis of HIV and the lung","volume":"10","author":"Gingo","year":"2013","journal-title":"Curr HIV\/AIDS Rep"},{"key":"2026032100244757600_bib2","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1164\/rccm.201006-0836OC","article-title":"HIV infection and risk for incident pulmonary diseases in the combination antiretroviral therapy era","volume":"183","author":"Crothers","year":"2011","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100244757600_bib3","first-page":"608","article-title":"Inflammatory responses in blood samples of human immunodeficiency virus-infected patients with pulmonary infections","volume":"11","author":"Benito","year":"2004","journal-title":"Clin Diagn Lab Immunol"},{"key":"2026032100244757600_bib4","first-page":"L256","article-title":"Production of interferon-gamma by lung lymphocytes in HIV-infected individuals","volume":"276","author":"Twigg","year":"1999","journal-title":"Am J Physiol"},{"key":"2026032100244757600_bib5","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1164\/ajrccm.159.5.9808031","article-title":"Lymphocytic alveolitis, bronchoalveolar lavage viral load, and outcome in human immunodeficiency virus infection","volume":"159","author":"Twigg","year":"1999","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100244757600_bib6","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1038\/nri1349","article-title":"Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity","volume":"4","author":"Chen","year":"2004","journal-title":"Nat Rev Immunol"},{"key":"2026032100244757600_bib7","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.coi.2009.01.010","article-title":"The diversity of costimulatory and inhibitory receptor pathways and the regulation of antiviral T cell responses","volume":"21","author":"Crawford","year":"2009","journal-title":"Curr Opin Immunol"},{"key":"2026032100244757600_bib8","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1146\/annurev.immunol.23.021704.115839","article-title":"TNF\/TNFR family members in costimulation of T cell responses","volume":"23","author":"Watts","year":"2005","journal-title":"Annu Rev Immunol"},{"key":"2026032100244757600_bib9","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1097\/COH.0b013e3282f9ae8b","article-title":"Programmed death-1 as a factor in immune exhaustion and activation in HIV infection","volume":"3","author":"Kaufmann","year":"2008","journal-title":"Curr Opin HIV AIDS"},{"key":"2026032100244757600_bib10","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1038\/ni1515","article-title":"Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction","volume":"8","author":"Kaufmann","year":"2007","journal-title":"Nat Immunol"},{"key":"2026032100244757600_bib11","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":"2026032100244757600_bib12","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":"2026032100244757600_bib13","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1038\/nm1482","article-title":"Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction","volume":"12","author":"Trautmann","year":"2006","journal-title":"Nat Med"},{"key":"2026032100244757600_bib14","doi-asserted-by":"crossref","first-page":"980","DOI":"10.4049\/jimmunol.182.2.980","article-title":"PD-1 blockade in rhesus macaques: impact on chronic infection and prophylactic vaccination","volume":"182","author":"Finnefrock","year":"2009","journal-title":"J Immunol"},{"key":"2026032100244757600_bib15","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.4049\/jimmunol.1300282","article-title":"Impaired function of CTLA-4 in the lungs of patients with chronic beryllium disease contributes to persistent inflammation","volume":"191","author":"Chain","year":"2013","journal-title":"J Immunol"},{"key":"2026032100244757600_bib16","doi-asserted-by":"crossref","first-page":"e77780","DOI":"10.1371\/journal.pone.0077780","article-title":"PD-1 blockade in chronically HIV-1-infected humanized mice suppresses viral loads","volume":"8","author":"Seung","year":"2013","journal-title":"PLoS ONE"},{"key":"2026032100244757600_bib17","doi-asserted-by":"crossref","first-page":"3007","DOI":"10.4049\/jimmunol.1000156","article-title":"Regulation of virus-specific CD4+ T cell function by multiple costimulatory receptors during chronic HIV infection","volume":"185","author":"Kassu","year":"2010","journal-title":"J Immunol"},{"key":"2026032100244757600_bib18","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1164\/rccm.201001-0025OC","article-title":"Deficient and dysfunctional regulatory T cells in the lungs of chronic beryllium disease subjects","volume":"181","author":"Mack","year":"2010","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100244757600_bib19","doi-asserted-by":"crossref","first-page":"2704","DOI":"10.4049\/jimmunol.180.4.2704","article-title":"Up-regulation of programmed death-1 expression on beryllium-specific CD4+ T cells in chronic beryllium disease","volume":"180","author":"Palmer","year":"2008","journal-title":"J Immunol"},{"key":"2026032100244757600_bib20","doi-asserted-by":"crossref","first-page":"963","DOI":"10.2307\/2529876","article-title":"Random-effects models for longitudinal data","volume":"38","author":"Laird","year":"1982","journal-title":"Biometrics"},{"key":"2026032100244757600_bib21","doi-asserted-by":"crossref","first-page":"5925","DOI":"10.1128\/JVI.76.12.5925-5936.2002","article-title":"Discordance between frequency of human immunodeficiency virus type 1 (HIV-1)-specific gamma interferon-producing CD4+ T cells and HIV-1-specific lymphoproliferation in HIV-1-infected subjects with active viral replication","volume":"76","author":"Palmer","year":"2002","journal-title":"J Virol"},{"key":"2026032100244757600_bib22","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1084\/jem.20031598","article-title":"HIV-1 viremia prevents the establishment of interleukin 2-producing HIV-specific memory CD4+ T cells endowed with proliferative capacity","volume":"198","author":"Younes","year":"2003","journal-title":"J Exp Med"},{"key":"2026032100244757600_bib23","doi-asserted-by":"crossref","first-page":"13878","DOI":"10.1073\/pnas.251539598","article-title":"High-level HIV-1 viremia suppresses viral antigen-specific CD4(+) T cell proliferation","volume":"98","author":"McNeil","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026032100244757600_bib24","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s11904-008-0003-7","article-title":"T-cell exhaustion in HIV infection","volume":"5","author":"El-Far","year":"2008","journal-title":"Curr HIV\/AIDS Rep"},{"key":"2026032100244757600_bib25","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1378\/chest.94.6.1264","article-title":"Human immunodeficiency virus-related lymphocytic alveolitis","volume":"94","author":"Guillon","year":"1988","journal-title":"Chest"},{"key":"2026032100244757600_bib26","first-page":"179","article-title":"Evidence for a cytotoxic T-lymphocyte alveolitis in human immunodeficiency virus-infected patients","volume":"2","author":"Autran","year":"1988","journal-title":"AIDS"},{"key":"2026032100244757600_bib27","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1164\/ajrccm.162.4.2003130","article-title":"CXC chemokines IP-10 and mig expression and direct migration of pulmonary CD8+\/CXCR3+ T cells in the lungs of patients with HIV infection and T-cell alveolitis","volume":"162","author":"Agostini","year":"2000","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100244757600_bib28","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1111\/j.1365-2249.1994.tb06540.x","article-title":"Alveolar macrophages from subjects infected with HIV-1 express macrophage inflammatory protein-1 alpha (MIP-1 alpha): contribution to the CD8+ alveolitis","volume":"96","author":"Denis","year":"1994","journal-title":"Clin Exp Immunol"},{"key":"2026032100244757600_bib29","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.ccm.2013.01.004","article-title":"Impact of antiretroviral therapy on lung immunology and inflammation","volume":"34","author":"Twigg","year":"2013","journal-title":"Clin Chest Med"},{"key":"2026032100244757600_bib30","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1002\/jlb.64.3.298","article-title":"HIV load in highly purified CD8+ T cells retrieved from pulmonary and blood compartments","volume":"64","author":"Semenzato","year":"1998","journal-title":"J Leukoc Biol"},{"key":"2026032100244757600_bib31","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/rmv.1772","article-title":"The lungs as anatomical reservoirs of HIV infection","volume":"24","author":"Costiniuk","year":"2014","journal-title":"Rev Med Virol"},{"key":"2026032100244757600_bib32","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/mi.2007.5","article-title":"High frequencies of polyfunctional HIV-specific T cells are associated with preservation of mucosal CD4 T cells in bronchoalveolar lavage","volume":"1","author":"Brenchley","year":"2008","journal-title":"Mucosal Immunol"},{"key":"2026032100244757600_bib33","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1038\/mi.2013.127","article-title":"Small alveolar macrophages are infected preferentially by HIV and exhibit impaired phagocytic function","volume":"7","author":"Jambo","year":"2014","journal-title":"Mucosal Immunol"},{"key":"2026032100244757600_bib34","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.tim.2013.05.001","article-title":"The HIV-1-containing macrophage compartment: a perfect cellular niche?","volume":"21","author":"Tan","year":"2013","journal-title":"Trends Microbiol"},{"key":"2026032100244757600_bib35","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.virol.2011.11.024","article-title":"Lymph nodes harbor viral reservoirs that cause rebound of plasma viremia in SIV-infected macaques upon cessation of combined antiretroviral therapy","volume":"423","author":"Horiike","year":"2012","journal-title":"Virology"},{"key":"2026032100244757600_bib36","doi-asserted-by":"crossref","first-page":"11876","DOI":"10.1128\/JVI.01153-09","article-title":"Defective human immunodeficiency virus-specific CD8+ T-cell polyfunctionality, proliferation, and cytotoxicity are not restored by antiretroviral therapy","volume":"83","author":"Migueles","year":"2009","journal-title":"J Virol"},{"key":"2026032100244757600_bib37","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.immuni.2007.09.006","article-title":"Molecular signature of CD8+ T cell exhaustion during chronic viral infection","volume":"27","author":"Wherry","year":"2007","journal-title":"Immunity"},{"key":"2026032100244757600_bib38","doi-asserted-by":"crossref","first-page":"1927","DOI":"10.1053\/j.gastro.2008.02.033","article-title":"Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization","volume":"134","author":"Nakamoto","year":"2008","journal-title":"Gastroenterology"}],"container-title":["American Journal of Respiratory and Critical Care Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/191\/4\/464\/67217479\/ajrccm_191_4_464.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/191\/4\/464\/67217479\/ajrccm_191_4_464.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T04:24:56Z","timestamp":1774067096000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrccm\/article\/191\/4\/464\/8505160"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,2]]},"references-count":38,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2015,2,15]]},"published-print":{"date-parts":[[2015,2,15]]}},"URL":"https:\/\/doi.org\/10.1164\/rccm.201408-1521oc","relation":{},"ISSN":["1073-449X","1535-4970"],"issn-type":[{"value":"1073-449X","type":"print"},{"value":"1535-4970","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,2]]},"published":{"date-parts":[[2015,2]]}}}