Whole genome deep sequencing of HIV-1 reveals the impact of early minor variants upon immune recognition during acute infection.
Deep 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...
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Public Library of Science (PLoS)
2012
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oai:doaj.org-article:7846f6a69b894bfaae962b545cdfe22c2021-11-18T06:04:41ZWhole genome deep sequencing of HIV-1 reveals the impact of early minor variants upon immune recognition during acute infection.1553-73661553-737410.1371/journal.ppat.1002529https://doaj.org/article/7846f6a69b894bfaae962b545cdfe22c2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22412369/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Deep 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.Matthew R HennChristian L BoutwellPatrick CharleboisNiall J LennonKaren A PowerAlexander R MacalaladAaron M BerlinChristine M MalboeufElizabeth M RyanSante GnerreMichael C ZodyRachel L ErlichLisa M GreenAndrew BericalYaoyu WangMonica CasaliHendrik StreeckAllyson K BloomTim DudekDamien TullyRuchi NewmanKaren L AxtenAdrianne D GladdenLaura BattisMichael KemperQiandong ZengTerrance P SheaSharvari GujjaCarmen ZedlackOlivier GasserChristian BranderChristoph HessHuldrych F GünthardZabrina L BrummeChanson J BrummeSuzane BaznerJenna RychertJake P TinsleyKen H MayerEric RosenbergFlorencia PereyraJoshua Z LevinSarah K YoungHeiko JessenMarcus AltfeldBruce W BirrenBruce D WalkerTodd M AllenPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 8, Iss 3, p e1002529 (2012) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Matthew R Henn Christian L Boutwell Patrick Charlebois Niall J Lennon Karen A Power Alexander R Macalalad Aaron M Berlin Christine M Malboeuf Elizabeth M Ryan Sante Gnerre Michael C Zody Rachel L Erlich Lisa M Green Andrew Berical Yaoyu Wang Monica Casali Hendrik Streeck Allyson K Bloom Tim Dudek Damien Tully Ruchi Newman Karen L Axten Adrianne D Gladden Laura Battis Michael Kemper Qiandong Zeng Terrance P Shea Sharvari Gujja Carmen Zedlack Olivier Gasser Christian Brander Christoph Hess Huldrych F Günthard Zabrina L Brumme Chanson J Brumme Suzane Bazner Jenna Rychert Jake P Tinsley Ken H Mayer Eric Rosenberg Florencia Pereyra Joshua Z Levin Sarah K Young Heiko Jessen Marcus Altfeld Bruce W Birren Bruce D Walker Todd M Allen Whole genome deep sequencing of HIV-1 reveals the impact of early minor variants upon immune recognition during acute infection. |
| description |
Deep 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. |
| format |
article |
| author |
Matthew R Henn Christian L Boutwell Patrick Charlebois Niall J Lennon Karen A Power Alexander R Macalalad Aaron M Berlin Christine M Malboeuf Elizabeth M Ryan Sante Gnerre Michael C Zody Rachel L Erlich Lisa M Green Andrew Berical Yaoyu Wang Monica Casali Hendrik Streeck Allyson K Bloom Tim Dudek Damien Tully Ruchi Newman Karen L Axten Adrianne D Gladden Laura Battis Michael Kemper Qiandong Zeng Terrance P Shea Sharvari Gujja Carmen Zedlack Olivier Gasser Christian Brander Christoph Hess Huldrych F Günthard Zabrina L Brumme Chanson J Brumme Suzane Bazner Jenna Rychert Jake P Tinsley Ken H Mayer Eric Rosenberg Florencia Pereyra Joshua Z Levin Sarah K Young Heiko Jessen Marcus Altfeld Bruce W Birren Bruce D Walker Todd M Allen |
| author_facet |
Matthew R Henn Christian L Boutwell Patrick Charlebois Niall J Lennon Karen A Power Alexander R Macalalad Aaron M Berlin Christine M Malboeuf Elizabeth M Ryan Sante Gnerre Michael C Zody Rachel L Erlich Lisa M Green Andrew Berical Yaoyu Wang Monica Casali Hendrik Streeck Allyson K Bloom Tim Dudek Damien Tully Ruchi Newman Karen L Axten Adrianne D Gladden Laura Battis Michael Kemper Qiandong Zeng Terrance P Shea Sharvari Gujja Carmen Zedlack Olivier Gasser Christian Brander Christoph Hess Huldrych F Günthard Zabrina L Brumme Chanson J Brumme Suzane Bazner Jenna Rychert Jake P Tinsley Ken H Mayer Eric Rosenberg Florencia Pereyra Joshua Z Levin Sarah K Young Heiko Jessen Marcus Altfeld Bruce W Birren Bruce D Walker Todd M Allen |
| author_sort |
Matthew R Henn |
| title |
Whole genome deep sequencing of HIV-1 reveals the impact of early minor variants upon immune recognition during acute infection. |
| title_short |
Whole genome deep sequencing of HIV-1 reveals the impact of early minor variants upon immune recognition during acute infection. |
| title_full |
Whole genome deep sequencing of HIV-1 reveals the impact of early minor variants upon immune recognition during acute infection. |
| title_fullStr |
Whole genome deep sequencing of HIV-1 reveals the impact of early minor variants upon immune recognition during acute infection. |
| title_full_unstemmed |
Whole genome deep sequencing of HIV-1 reveals the impact of early minor variants upon immune recognition during acute infection. |
| title_sort |
whole genome deep sequencing of hiv-1 reveals the impact of early minor variants upon immune recognition during acute infection. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/7846f6a69b894bfaae962b545cdfe22c |
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