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dc.contributor.authorBrumme, Zabrina L
dc.contributor.authorAnastario, Michael
dc.contributor.authorCohen, Kristin W
dc.contributor.authorJolin, Jonathan S
dc.contributor.authorBrumme, Chanson J
dc.contributor.authorStreeck, Hendrik
dc.contributor.authorMeier, Angela
dc.contributor.authorRosenberg, Eric Scott
dc.contributor.authorAlter, Galit
dc.contributor.authorAllen, Todd
dc.contributor.authorWalker, Bruce David
dc.contributor.authorAltfeld, Marcus
dc.date.accessioned2011-05-09T23:55:19Z
dc.date.issued2008
dc.identifier.citationStreeck, Hendrik, Zabrina L. Brumme, Michael Anastario, Kristin W. Cohen, Jonathan S. Jolin, Angela Meier, Chanson J. Brumme, et al. 2008. Antigen Load and Viral Sequence Diversification Determine the Functional Profile of HIV-1 - Specific CD8+ T Cells. PLoS Medicine 5(5): e100.en_US
dc.identifier.issn1549-1277en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:4885941
dc.description.abstractBackground: Virus-specific CD8+ T lymphocytes play a key role in the initial reduction of peak viremia during acute viral infections, but display signs of increasing dysfunction and exhaustion under conditions of chronic antigen persistence. It has been suggested that virus-specific CD8+ T cells with a “polyfunctional” profile, defined by the capacity to secrete multiple cytokines or chemokines, are most competent in controlling viral replication in chronic HIV-1 infection. We used HIV-1 infection as a model of chronic persistent viral infection to investigate the process of exhaustion and dysfunction of virus-specific CD8+ T cell responses on the single-epitope level over time, starting in primary HIV-1 infection. Methods and Findings: We longitudinally analyzed the polyfunctional epitope-specific CD8+ T cell responses of 18 patients during primary HIV-1 infection before and after therapy initiation or sequence variation in the targeted epitope. Epitope-specific CD8+ T cells responded with multiple effector functions to antigenic stimulation during primary HIV-1 infection, but lost their polyfunctional capacity in response to antigen and up-regulated programmed death 1 (PD-1) expression with persistent viremic infection. This exhausted phenotype significantly decreased upon removal of stimulation by antigen, either in response to antiretroviral therapy or by reduction of epitope-specific antigen load in the presence of ongoing viral replication, as a consequence of in vivo selection of cytotoxic T lymphocyte escape mutations in the respective epitopes. Monofunctionality increased in CD8+ T cell responses directed against conserved epitopes from 49% (95% confidence interval 27%–72%) to 76% (56%–95%) (standard deviation [SD] of the effect size 0.71), while monofunctionality remained stable or slightly decreased for responses directed against escaped epitopes from 61% (47%–75%) to 56% (42%–70%) (SD of the effect size 0.18) (p < 0.05). Conclusion: These data suggest that persistence of antigen can be the cause, rather than the consequence, of the functional impairment of virus-specific T cell responses observed during chronic HIV-1 infection, and underscore the importance of evaluating autologous viral sequences in studies aimed at investigating the relationship between virus-specific immunity and associated pathogenesis.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pmed.0050100en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2365971/pdf/en_US
dash.licenseLAA
dc.subjectimmunologyen_US
dc.subjectinfectious diseasesen_US
dc.subjectHIV infectionen_US
dc.subjectAIDSen_US
dc.subjectimmunology and allergyen_US
dc.titleAntigen Load and Viral Sequence Diversification Determine the Functional Profile of HIV-1–Specific CD8+ T Cellsen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS Medicineen_US
dash.depositing.authorAlter, Galit
dc.date.available2011-05-09T23:55:19Z
dash.affiliation.otherHMS^Medicine-Massachusetts General Hospitalen_US
dash.affiliation.otherHMS^Medicine-Massachusetts General Hospitalen_US
dash.affiliation.otherHMS^Medicine-Massachusetts General Hospitalen_US
dash.affiliation.otherHMS^Medicine-Massachusetts General Hospitalen_US
dash.affiliation.otherSPH^Immunology and Infectious Diseasesen_US
dash.affiliation.otherHMS^Medicine-Massachusetts General Hospitalen_US
dc.identifier.doi10.1371/journal.pmed.0050100*
dash.authorsorderedfalse
dash.contributor.affiliatedMeier, Angela
dash.contributor.affiliatedStreeck, Hendrik
dash.contributor.affiliatedAltfeld, Marcus
dash.contributor.affiliatedAllen, Todd
dash.contributor.affiliatedRosenberg, Eric
dash.contributor.affiliatedAlter, Galit
dash.contributor.affiliatedWalker, Bruce
dc.identifier.orcid0000-0001-6122-9245


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