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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Main Authors:	Henn, Matthew R., Boutwell, Christian L., Charlebois, Patrick, Lennon, Niall J., Power, Karen A., Macalalad, Alexander R., Berlin, Aaron M., Malboeuf, Christine M., Ryan, Elizabeth M., Gnerre, Sante, Zody, Michael C., Erlich, Rachel L., Green, Lisa M., Berical, Andrew, Wang, Yaoyu, Casali, Monica, Streeck, Hendrik, Bloom, Allyson K., Dudek, Tim, Tully, Damien, Newman, Ruchi, Axten, Karen L., Gladden, Adrianne D., Battis, Laura, Kemper, Michael, Zeng, Qiandong, Shea, Terrance P., Gujja, Sharvari, Zedlack, Carmen, Gasser, Olivier, Brander, Christian, Hess, Christoph, Günthard, Huldrych F., Brumme, Zabrina L., Brumme, Chanson J., Bazner, Suzane, Rychert, Jenna, Tinsley, Jake P., Mayer, Ken H., Rosenberg, Eric, Pereyra, Florencia, Levin, Joshua Z., Young, Sarah K., Jessen, Heiko, Altfeld, Marcus, Birren, Bruce W., Walker, Bruce D., Allen, Todd M.
Format:	Online
Language:	English
Published:	Public Library of Science 2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297584/

id	pubmed-3297584
recordtype	oai_dc
spelling	pubmed-32975842012-03-12 Whole Genome Deep Sequencing of HIV-1 Reveals the Impact of Early Minor Variants Upon Immune Recognition During Acute Infection Henn, Matthew R. Boutwell, Christian L. Charlebois, Patrick Lennon, Niall J. Power, Karen A. Macalalad, Alexander R. Berlin, Aaron M. Malboeuf, Christine M. Ryan, Elizabeth M. Gnerre, Sante Zody, Michael C. Erlich, Rachel L. Green, Lisa M. Berical, Andrew Wang, Yaoyu Casali, Monica Streeck, Hendrik Bloom, Allyson K. Dudek, Tim Tully, Damien Newman, Ruchi Axten, Karen L. Gladden, Adrianne D. Battis, Laura Kemper, Michael Zeng, Qiandong Shea, Terrance P. Gujja, Sharvari Zedlack, Carmen Gasser, Olivier Brander, Christian Hess, Christoph Günthard, Huldrych F. Brumme, Zabrina L. Brumme, Chanson J. Bazner, Suzane Rychert, Jenna Tinsley, Jake P. Mayer, Ken H. Rosenberg, Eric Pereyra, Florencia Levin, Joshua Z. Young, Sarah K. Jessen, Heiko Altfeld, Marcus Birren, Bruce W. Walker, Bruce D. Allen, Todd M. Research Article 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. Public Library of Science 2012-03-08 /pmc/articles/PMC3297584/ /pubmed/22412369 http://dx.doi.org/10.1371/journal.ppat.1002529 Text en Henn et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Henn, Matthew R. Boutwell, Christian L. Charlebois, Patrick Lennon, Niall J. Power, Karen A. Macalalad, Alexander R. Berlin, Aaron M. Malboeuf, Christine M. Ryan, Elizabeth M. Gnerre, Sante Zody, Michael C. Erlich, Rachel L. Green, Lisa M. Berical, Andrew Wang, Yaoyu Casali, Monica Streeck, Hendrik Bloom, Allyson K. Dudek, Tim Tully, Damien Newman, Ruchi Axten, Karen L. Gladden, Adrianne D. Battis, Laura Kemper, Michael Zeng, Qiandong Shea, Terrance P. Gujja, Sharvari Zedlack, Carmen Gasser, Olivier Brander, Christian Hess, Christoph Günthard, Huldrych F. Brumme, Zabrina L. Brumme, Chanson J. Bazner, Suzane Rychert, Jenna Tinsley, Jake P. Mayer, Ken H. Rosenberg, Eric Pereyra, Florencia Levin, Joshua Z. Young, Sarah K. Jessen, Heiko Altfeld, Marcus Birren, Bruce W. Walker, Bruce D. Allen, Todd M.
spellingShingle	Henn, Matthew R. Boutwell, Christian L. Charlebois, Patrick Lennon, Niall J. Power, Karen A. Macalalad, Alexander R. Berlin, Aaron M. Malboeuf, Christine M. Ryan, Elizabeth M. Gnerre, Sante Zody, Michael C. Erlich, Rachel L. Green, Lisa M. Berical, Andrew Wang, Yaoyu Casali, Monica Streeck, Hendrik Bloom, Allyson K. Dudek, Tim Tully, Damien Newman, Ruchi Axten, Karen L. Gladden, Adrianne D. Battis, Laura Kemper, Michael Zeng, Qiandong Shea, Terrance P. Gujja, Sharvari Zedlack, Carmen Gasser, Olivier Brander, Christian Hess, Christoph Günthard, Huldrych F. Brumme, Zabrina L. Brumme, Chanson J. Bazner, Suzane Rychert, Jenna Tinsley, Jake P. Mayer, Ken H. Rosenberg, Eric Pereyra, Florencia Levin, Joshua Z. Young, Sarah K. Jessen, Heiko Altfeld, Marcus Birren, Bruce W. Walker, Bruce D. Allen, Todd M. Whole Genome Deep Sequencing of HIV-1 Reveals the Impact of Early Minor Variants Upon Immune Recognition During Acute Infection
author_facet	Henn, Matthew R. Boutwell, Christian L. Charlebois, Patrick Lennon, Niall J. Power, Karen A. Macalalad, Alexander R. Berlin, Aaron M. Malboeuf, Christine M. Ryan, Elizabeth M. Gnerre, Sante Zody, Michael C. Erlich, Rachel L. Green, Lisa M. Berical, Andrew Wang, Yaoyu Casali, Monica Streeck, Hendrik Bloom, Allyson K. Dudek, Tim Tully, Damien Newman, Ruchi Axten, Karen L. Gladden, Adrianne D. Battis, Laura Kemper, Michael Zeng, Qiandong Shea, Terrance P. Gujja, Sharvari Zedlack, Carmen Gasser, Olivier Brander, Christian Hess, Christoph Günthard, Huldrych F. Brumme, Zabrina L. Brumme, Chanson J. Bazner, Suzane Rychert, Jenna Tinsley, Jake P. Mayer, Ken H. Rosenberg, Eric Pereyra, Florencia Levin, Joshua Z. Young, Sarah K. Jessen, Heiko Altfeld, Marcus Birren, Bruce W. Walker, Bruce D. Allen, Todd M.
author_sort	Henn, Matthew R.
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
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.
publisher	Public Library of Science
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297584/
_version_	1611511650320384000

Whole Genome Deep Sequencing of HIV-1 Reveals the Impact of Early Minor Variants Upon Immune Recognition During Acute Infection

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