Transmission of single HIV-1 genomes and dynamics of early immune escape revealed by ultra-deep sequencing.

We used ultra-deep sequencing to obtain tens of thousands of HIV-1 sequences from regions targeted by CD8+ T lymphocytes from longitudinal samples from three acutely infected subjects, and modeled viral evolution during the critical first weeks of infection. Previous studies suggested that a single...

Celý popis

Podrobná bibliografie
Hlavní autoři: Fischer, W, Ganusov, V, Giorgi, E, Hraber, P, Keele, B, Leitner, T, Han, C, Gleasner, C, Green, L, Lo, C, Nag, A, Wallstrom, T, Wang, S, McMichael, A, Haynes, B, Hahn, B, Perelson, A, Borrow, P, Shaw, G, Bhattacharya, T, Korber, B
Médium: Journal article
Jazyk:English
Vydáno: Public Library of Science 2010
_version_ 1826268306030460928
author Fischer, W
Ganusov, V
Giorgi, E
Hraber, P
Keele, B
Leitner, T
Han, C
Gleasner, C
Green, L
Lo, C
Nag, A
Wallstrom, T
Wang, S
McMichael, A
Haynes, B
Hahn, B
Perelson, A
Borrow, P
Shaw, G
Bhattacharya, T
Korber, B
author_facet Fischer, W
Ganusov, V
Giorgi, E
Hraber, P
Keele, B
Leitner, T
Han, C
Gleasner, C
Green, L
Lo, C
Nag, A
Wallstrom, T
Wang, S
McMichael, A
Haynes, B
Hahn, B
Perelson, A
Borrow, P
Shaw, G
Bhattacharya, T
Korber, B
author_sort Fischer, W
collection OXFORD
description We used ultra-deep sequencing to obtain tens of thousands of HIV-1 sequences from regions targeted by CD8+ T lymphocytes from longitudinal samples from three acutely infected subjects, and modeled viral evolution during the critical first weeks of infection. Previous studies suggested that a single virus established productive infection, but these conclusions were tempered because of limited sampling; now, we have greatly increased our confidence in this observation through modeling the observed earliest sample diversity based on vastly more extensive sampling. Conventional sequencing of HIV-1 from acute/early infection has shown different patterns of escape at different epitopes; we investigated the earliest escapes in exquisite detail. Over 3-6 weeks, ultradeep sequencing revealed that the virus explored an extraordinary array of potential escape routes in the process of evading the earliest CD8 T-lymphocyte responses--using 454 sequencing, we identified over 50 variant forms of each targeted epitope during early immune escape, while only 2-7 variants were detected in the same samples via conventional sequencing. In contrast to the diversity seen within epitopes, non-epitope regions, including the Envelope V3 region, which was sequenced as a control in each subject, displayed very low levels of variation. In early infection, in the regions sequenced, the consensus forms did not have a fitness advantage large enough to trigger reversion to consensus amino acids in the absence of immune pressure. In one subject, a genetic bottleneck was observed, with extensive diversity at the second time point narrowing to two dominant escape forms by the third time point, all within two months of infection. Traces of immune escape were observed in the earliest samples, suggesting that immune pressure is present and effective earlier than previously reported; quantifying the loss rate of the founder virus suggests a direct role for CD8 T-lymphocyte responses in viral containment after peak viremia. Dramatic shifts in the frequencies of epitope variants during the first weeks of infection revealed a complex interplay between viral fitness and immune escape.
first_indexed 2024-03-06T21:07:39Z
format Journal article
id oxford-uuid:3d0509b8-587a-4bd3-ac2a-970d0180944c
institution University of Oxford
language English
last_indexed 2024-03-06T21:07:39Z
publishDate 2010
publisher Public Library of Science
record_format dspace
spelling oxford-uuid:3d0509b8-587a-4bd3-ac2a-970d0180944c2022-03-26T14:17:06ZTransmission of single HIV-1 genomes and dynamics of early immune escape revealed by ultra-deep sequencing.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:3d0509b8-587a-4bd3-ac2a-970d0180944cEnglishSymplectic Elements at OxfordPublic Library of Science2010Fischer, WGanusov, VGiorgi, EHraber, PKeele, BLeitner, THan, CGleasner, CGreen, LLo, CNag, AWallstrom, TWang, SMcMichael, AHaynes, BHahn, BPerelson, ABorrow, PShaw, GBhattacharya, TKorber, BWe used ultra-deep sequencing to obtain tens of thousands of HIV-1 sequences from regions targeted by CD8+ T lymphocytes from longitudinal samples from three acutely infected subjects, and modeled viral evolution during the critical first weeks of infection. Previous studies suggested that a single virus established productive infection, but these conclusions were tempered because of limited sampling; now, we have greatly increased our confidence in this observation through modeling the observed earliest sample diversity based on vastly more extensive sampling. Conventional sequencing of HIV-1 from acute/early infection has shown different patterns of escape at different epitopes; we investigated the earliest escapes in exquisite detail. Over 3-6 weeks, ultradeep sequencing revealed that the virus explored an extraordinary array of potential escape routes in the process of evading the earliest CD8 T-lymphocyte responses--using 454 sequencing, we identified over 50 variant forms of each targeted epitope during early immune escape, while only 2-7 variants were detected in the same samples via conventional sequencing. In contrast to the diversity seen within epitopes, non-epitope regions, including the Envelope V3 region, which was sequenced as a control in each subject, displayed very low levels of variation. In early infection, in the regions sequenced, the consensus forms did not have a fitness advantage large enough to trigger reversion to consensus amino acids in the absence of immune pressure. In one subject, a genetic bottleneck was observed, with extensive diversity at the second time point narrowing to two dominant escape forms by the third time point, all within two months of infection. Traces of immune escape were observed in the earliest samples, suggesting that immune pressure is present and effective earlier than previously reported; quantifying the loss rate of the founder virus suggests a direct role for CD8 T-lymphocyte responses in viral containment after peak viremia. Dramatic shifts in the frequencies of epitope variants during the first weeks of infection revealed a complex interplay between viral fitness and immune escape.
spellingShingle Fischer, W
Ganusov, V
Giorgi, E
Hraber, P
Keele, B
Leitner, T
Han, C
Gleasner, C
Green, L
Lo, C
Nag, A
Wallstrom, T
Wang, S
McMichael, A
Haynes, B
Hahn, B
Perelson, A
Borrow, P
Shaw, G
Bhattacharya, T
Korber, B
Transmission of single HIV-1 genomes and dynamics of early immune escape revealed by ultra-deep sequencing.
title Transmission of single HIV-1 genomes and dynamics of early immune escape revealed by ultra-deep sequencing.
title_full Transmission of single HIV-1 genomes and dynamics of early immune escape revealed by ultra-deep sequencing.
title_fullStr Transmission of single HIV-1 genomes and dynamics of early immune escape revealed by ultra-deep sequencing.
title_full_unstemmed Transmission of single HIV-1 genomes and dynamics of early immune escape revealed by ultra-deep sequencing.
title_short Transmission of single HIV-1 genomes and dynamics of early immune escape revealed by ultra-deep sequencing.
title_sort transmission of single hiv 1 genomes and dynamics of early immune escape revealed by ultra deep sequencing
work_keys_str_mv AT fischerw transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing
AT ganusovv transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing
AT giorgie transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing
AT hraberp transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing
AT keeleb transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing
AT leitnert transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing
AT hanc transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing
AT gleasnerc transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing
AT greenl transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing
AT loc transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing
AT naga transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing
AT wallstromt transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing
AT wangs transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing
AT mcmichaela transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing
AT haynesb transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing
AT hahnb transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing
AT perelsona transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing
AT borrowp transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing
AT shawg transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing
AT bhattacharyat transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing
AT korberb transmissionofsinglehiv1genomesanddynamicsofearlyimmuneescaperevealedbyultradeepsequencing