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Title: Transmission of Single HIV-1 Genomes and Dynamics of Early Immune Escape Revealed by Ultra-Deep Sequencing

Journal Article · · PLoS ONE
 [1];  [2];  [3];  [1];  [4];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [5];  [6];  [7];  [5];  [1];  [8];  [5];  [9] more »;  [10] « less
  1. Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
  2. Los Alamos National Laboratory (LANL), Los Alamos, NM (United States); University of Tennessee, Knoxville, TN (United States)
  3. Los Alamos National Laboratory (LANL), Los Alamos, NM (United States); University of Massachusetts, Amherst, MA (United States)
  4. SAIC-Frederick, Frederick, MD (United States)
  5. University of Alabama, Birmingham, AL (United States)
  6. Oxford University (United Kingdom)
  7. Duke University, Durham, NC (United States)
  8. University of Oxford (United Kingdom)
  9. Los Alamos National Laboratory (LANL), Los Alamos, NM (United States; Santa Fe Institute (SFI), Santa Fe, NM (United States)
  10. Los Alamos National Laboratory (LANL), Los Alamos, NM (United States); Santa Fe Institute (SFI), Santa Fe, NM (United States)
+ Show Author Affiliations

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.

Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER); USDOE Laboratory Directed Research and Development (LDRD) Program; Bill and Melinda Gates Foundation; National Institutes of Health (NIH)
Grant/Contract Number:
AC52-06NA25396; AI-0678501; 37874
OSTI ID:
1627420
Journal Information:
PLoS ONE, Vol. 5, Issue 8; ISSN 1932-6203
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

References (54)

The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection journal June 2009
Higher Set Point Plasma Viral Load and More-Severe Acute HIV Type 1 (HIV-1) Illness Predict Mortality among High-Risk HIV-1-Infected African Women journal May 2006
Quantitating the Multiplicity of Infection with Human Immunodeficiency Virus Type 1 Subtype C Reveals a Non-Poisson Distribution of Transmitted Variants text January 2009
Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection journal June 2009
Mutations of Bacteria from Virus Sensitivity to Virus Resistance journal November 1943
Wide Variation in the Multiplicity of HIV-1 Infection among Injection Drug Users journal April 2010
Fitness Constraints on Immune Escape from HIV: Implications of Envelope as a Target for Both HIV-Specific T Cells and Antibody journal April 2006
Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection journal May 2008
Quantitative Deep Sequencing Reveals Dynamic HIV-1 Escape and Large Population Shifts during CCR5 Antagonist Therapy In Vivo journal May 2009
HIV Evolution in Early Infection: Selection Pressures, Patterns of Insertion and Deletion, and the Impact of APOBEC journal May 2009
Rare HLA Drive Additional HIV Evolution Compared to More Frequent Alleles journal March 2009
High Multiplicity Infection by HIV-1 in Men Who Have Sex with Men journal May 2010
A New Perspective on V3 Phenotype Prediction journal February 2003
Transmission and Long-Term Stability of Compensated CD8 Escape Mutations journal December 2008
Antiviral pressure exerted by HIV-l-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus journal February 1997
Hepatitis C Virus Transmission Bottlenecks Analyzed by Deep Sequencing journal April 2010
Estimating Costs and Benefits of CTL Escape Mutations in SIV/HIV Infection journal January 2005
Modeling sequence evolution in acute HIV-1 infection journal November 2009
Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection text January 2009
Inefficient Cytotoxic T Lymphocyte–Mediated Killing of HIV-1–Infected Cells In Vivo journal March 2006
Estimating Costs and Benefits of CTL Escape Mutations in SIV/HIV Infection journal March 2006
Mosaic vaccines elicit CD8+ T lymphocyte responses that confer enhanced immune coverage of diverse HIV strains in monkeys journal February 2010
Influence of combinations of human major histocompatibility complex genes on the course of HIV–1 infection journal April 1996
The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection text January 2009
Systematic artifacts in metagenomes from complex microbial communities journal July 2009
HIV-1 Dynamics in Vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time journal March 1996
Determinants of Human Immunodeficiency Virus Type 1 Escape from the Primary CD8+ Cytotoxic T Lymphocyte Response journal November 2004
Evolution of HLA-B*5703 HIV-1 escape mutations in HLA-B*5703–positive individuals and their transmission recipients journal March 2009
Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection
  • F., Salazar-Gonzalez, Jesus; P., Busch, Michael; S., Perelson, Alan
  • The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/f6s9-vz03
text January 2008
Adaptive Evolution of Human Immunodeficiency Virus-Type 1 During the Natural Course of Infection journal April 1996
Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants journal December 2006
Immune control of an SIV challenge by a T-cell-based vaccine in rhesus monkeys journal November 2008
Mathematical modeling of ultradeep sequencing data reveals that acute CD8+ T-lymphocyte responses exert strong selective pressure in simian immunodeficiency virus-infected macaques but still fail to clear founder epitope sequences. journal June 2010
Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. journal January 1994
Evidence of Differential HLA Class I-Mediated Viral Evolution in Functional and Accessory/Regulatory Genes of HIV-1 journal July 2007
Accurate determination of microbial diversity from 454 pyrosequencing data journal August 2009
Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys journal February 2010
High Multiplicity Infection by HIV-1 in Men Who Have Sex with Men text January 2010
Quantitating the Multiplicity of Infection with Human Immunodeficiency Virus Type 1 Subtype C Reveals a Non-Poisson Distribution of Transmitted Variants journal July 2009
Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection
  • S., Perelson, Alan; Christina, Ochsenbauer-Jambor,; C., Kappas, John
  • The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/1n1a-3d64
text January 2009
Genome sequencing in microfabricated high-density picolitre reactors journal July 2005
A unified view of polymer, dumbbell, and oligonucleotide DNA nearest-neighbor thermodynamics journal February 1998
APE: Analyses of Phylogenetics and Evolution in R language journal January 2004
A Simple, Fast, and Accurate Algorithm to Estimate Large Phylogenies by Maximum Likelihood journal October 2003
A guided tour to approximate string matching journal March 2001
HIV-1 Epitope-Specific CD8 + T Cell Responses Strongly Associated with Delayed Disease Progression Cross-Recognize Epitope Variants Efficiently journal May 2006
HIV and HLA: Confusion or complexity? journal April 1996
The 'rare biosphere': a reality check journal September 2009
AIDS Pathogenesis: A Finite Immune Response to Blame? journal April 1996
Mathematical Modeling of Ultradeep Sequencing Data Reveals that Acute CD8+ T-Lymphocyte Responses Exert Strong Selective Pressure in Simian Immunodeficiency Virus-Infected Macaques but Still Fail To Clear Founder Epitope Sequences journal March 2010
Ultradeep Pyrosequencing Detects Complex Patterns of CD8+ T-Lymphocyte Escape in Simian Immunodeficiency Virus-Infected Macaques journal June 2009
Marked Epitope- and Allele-Specific Differences in Rates of Mutation in Human Immunodeficiency Type 1 (HIV-1) Gag, Pol, and Nef Cytotoxic T-Lymphocyte Epitopes in Acute/Early HIV-1 Infection journal July 2008
Genetic differences between blood- and brain-derived viral sequences from human immunodeficiency virus type 1-infected patients: evidence of conserved elements in the V3 region of the envelope protein of brain-derived sequences. journal January 1994
Inefficient Immune Killer Cells Abet HIV Infection journal March 2006

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Temporal Dynamics of CD8+ T Cell Effector Responses during Primary HIV Infection journal August 2016
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Full-Length Envelope Analyzer (FLEA): A tool for longitudinal analysis of viral amplicons journal December 2018
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Detection of Minority Resistance during Early HIV-1 Infection: Natural Variation and Spurious Detection rather than Transmission and Evolution of Multiple Viral Variants journal August 2011
Rare HIV-1 transmitted/founder lineages identified by deep viral sequencing contribute to rapid shifts in dominant quasispecies during acute and early infection text January 2017
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Bottlenecks in HIV-1 transmission: insights from the study of founder viruses text January 2015
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Epigraph: A Vaccine Design Tool Applied to an HIV Therapeutic Vaccine and a Pan-Filovirus Vaccine journal October 2016
Balance between transmitted HLA preadapted and nonassociated polymorphisms is a major determinant of HIV-1 disease progression journal August 2016
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Restriction of V3 region sequence divergence in the HIV-1 envelope gene during antiretroviral treatment in a cohort of recent seroconverters journal January 2013
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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
phylogenetic analysis
viral replication
immune response
T cells
microbial mutation
viral load
natural selection
polymerase chain reaction