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dc.contributor.authorHenn, Matthew R.
dc.contributor.authorCharlebois, Patrick
dc.contributor.authorLennon, Niall J.
dc.contributor.authorPower, Karen A.
dc.contributor.authorMacalalad, Alexander R.
dc.contributor.authorBerlin, Aaron M.
dc.contributor.authorMalboeuf, Christine M.
dc.contributor.authorGnerre, Sante
dc.contributor.authorErlich, Rachel L.
dc.contributor.authorGreen, Lisa M.
dc.contributor.authorBerical, Andrew
dc.contributor.authorWang, Yaoyu
dc.contributor.authorNewman, Ruchi
dc.contributor.authorAxten, Karen L.
dc.contributor.authorGladden, Adrianne D.
dc.contributor.authorBattis, Laura
dc.contributor.authorKemper, Michael
dc.contributor.authorZeng, Qiandong
dc.contributor.authorShea, Terrance P.
dc.contributor.authorGujja, Sharvari
dc.contributor.authorZedlack, Carmen
dc.contributor.authorGasser, Olivier
dc.contributor.authorBrander, Christian
dc.contributor.authorGünthard, Huldrych F.
dc.contributor.authorBrumme, Zabrina L.
dc.contributor.authorBrumme, Chanson J.
dc.contributor.authorBazner, Suzane
dc.contributor.authorRychert, Jenna
dc.contributor.authorTinsley, Jake P.
dc.contributor.authorLevin, Joshua Z.
dc.contributor.authorJessen, Heiko
dc.contributor.authorBirren, Bruce W.
dc.contributor.authorBoutwell, Christian Lane
dc.contributor.authorRyan, Elizabeth M.
dc.contributor.authorZody, Michael C.
dc.contributor.authorCasali, Monica
dc.contributor.authorStreeck, Hendrik
dc.contributor.authorBloom, Allyson Kelly
dc.contributor.authorDudek, Timothy E.
dc.contributor.authorTully, Damien C.
dc.contributor.authorHess, Christoph
dc.contributor.authorMayer, Kenneth Hugh
dc.contributor.authorRosenberg, Eric Scott
dc.contributor.authorPereyra, Florencia M.
dc.contributor.authorYoung, Sarah K.
dc.contributor.authorAltfeld, Marcus
dc.contributor.authorWalker, Bruce David
dc.contributor.authorAllen, Todd
dc.date.accessioned2013-02-19T16:40:38Z
dc.date.issued2012
dc.identifier.citationHenn, Matthew R., Christian L. Boutwell, Patrick Charlebois, Niall J. Lennon, Karen A. Power, Alexander R. Macalalad, Aaron M. Berlin, et al. 2012. Whole genome deep sequencing of HIV-1 reveals the impact of early minor variants upon immune recognition during acute infection. PLoS Pathogens 8(3): e1002529.en_US
dc.identifier.issn1553-7366en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10304558
dc.description.abstractDeep sequencing technologies have the potential to transform the study of highly variable viral pathogens by providing a rapid and cost-effective approach to sensitively characterize rapidly evolving viral quasispecies. Here, we report on a high-throughput whole HIV-1 genome deep sequencing platform that combines 454 pyrosequencing with novel assembly and variant detection algorithms. In one subject we combined these genetic data with detailed immunological analyses to comprehensively evaluate viral evolution and immune escape during the acute phase of HIV-1 infection. The majority of early, low frequency mutations represented viral adaptation to host CD8+ T cell responses, evidence of strong immune selection pressure occurring during the early decline from peak viremia. CD8+ T cell responses capable of recognizing these low frequency escape variants coincided with the selection and evolution of more effective secondary HLA-anchor escape mutations. Frequent, and in some cases rapid, reversion of transmitted mutations was also observed across the viral genome. When located within restricted CD8 epitopes these low frequency reverting mutations were sufficient to prime de novo responses to these epitopes, again illustrating the capacity of the immune response to recognize and respond to low frequency variants. More importantly, rapid viral escape from the most immunodominant CD8+ T cell responses coincided with plateauing of the initial viral load decline in this subject, suggestive of a potential link between maintenance of effective, dominant CD8 responses and the degree of early viremia reduction. We conclude that the early control of HIV-1 replication by immunodominant CD8+ T cell responses may be substantially influenced by rapid, low frequency viral adaptations not detected by conventional sequencing approaches, which warrants further investigation. These data support the critical need for vaccine-induced CD8+ T cell responses to target more highly constrained regions of the virus in order to ensure the maintenance of immunodominant CD8 responses and the sustained decline of early viremia.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.ppat.1002529en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297584/pdf/en_US
dash.licenseLAA
dc.subjectHIVen_US
dc.subjectbiologyen_US
dc.subjectimmunologyen_US
dc.subjectimmunityen_US
dc.subjectmedicineen_US
dc.subjectclinical immunologyen_US
dc.subjectimmune cellsen_US
dc.subjectinfectious diseasesen_US
dc.subjectviral diseasesen_US
dc.titleWhole Genome Deep Sequencing of HIV-1 Reveals the Impact of Early Minor Variants Upon Immune Recognition During Acute Infectionen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS Pathogensen_US
dash.depositing.authorStreeck, Hendrik
dc.date.available2013-02-19T16:40:38Z
dc.identifier.doi10.1371/journal.ppat.1002529*
dash.authorsorderedfalse
dash.contributor.affiliatedBloom, Allyson
dash.contributor.affiliatedZody, M
dash.contributor.affiliatedTully, Damien C
dash.contributor.affiliatedDudek, Timothy E
dash.contributor.affiliatedCasali, Monica
dash.contributor.affiliatedStreeck, Hendrik
dash.contributor.affiliatedAltfeld, Marcus
dash.contributor.affiliatedAllen, Todd
dash.contributor.affiliatedBoutwell, C
dash.contributor.affiliatedMayer, Kenneth
dash.contributor.affiliatedPereyra, F
dash.contributor.affiliatedWalker, Bruce
dash.contributor.affiliatedRosenberg, Eric
dc.identifier.orcid0000-0001-7460-733X
dc.identifier.orcid0000-0001-6122-9245


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