Whole genome deep sequencing of HIV-1 reveals the impact of early minor variants upon immune recognition during acute infection

Henn, M. R. and Boutwell, C. L. and Charlebois, P. and Lennon, N. J. and Power, K. A. and Macalalad, A. R. and Berlin, A. M. and Malboeuf, C. M. and Ryan, E. M. and Gnerre, S. and Zody, M. C. and Erlich, R. L. and Green, L. M. and Berical, A. and Wang, Y. and Casali, M. and Streeck, H. and Bloom, A. K. and Dudek, T. and Tully, D. and Newman, R. and Axten, K. L. and Gladden, A. D. and Battis, L. and Kemper, M. and Zeng, Q. and Shea, T. P. and Gujja, S. and Zedlack, C. and Gasser, O. and Brander, C. and Hess, C. and Gunthard, H. F. and Brumme, Z. L. and Brumme, C. J. and Bazner, S. and Rychert, J. and Tinsley, J. P. and Mayer, K. H. and Rosenberg, E. and Pereyra, F. and Levin, J. Z. and Young, S. K. and Jessen, H. and Altfeld, M. and Birren, B. W. and Walker, B. D. and Allen, T. M.. (2012) Whole genome deep sequencing of HIV-1 reveals the impact of early minor variants upon immune recognition during acute infection. PLoS Pathogens, Vol. 8, H. 3 , e1002529.

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Official URL: http://edoc.unibas.ch/dok/A6338508

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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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Immunobiology (Hess C)
UniBasel Contributors:Hess, Christoph
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Public Library of Science
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:13 Oct 2017 07:48
Deposited On:08 May 2015 08:45

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