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Title: HIV Evolution in Early Infection: Selection Pressures, Patterns of Insertion and Deletion, and the Impact of APOBEC

Journal Article · · PLoS Pathogens
 [1];  [2];  [3];  [4];  [5];  [6];  [6];  [7];  [7];  [5];  [3];  [3];  [2];  [8]
  1. University of Cape Town (South Africa); Centre for High Performance Computing (CHPR), Cape Town (South Africa)
  2. Los Alamos National Laboratory (LANL), Los Alamos, NM (United States); Santa Fe Institute (SFI), Santa Fe, NM (United States)
  3. University of Alabama, Birmingham, AL (United States)
  4. Los Alamos National Laboratory (LANL), Los Alamos, NM (United States); University of Massachusetts, Amherst, MA (United States)
  5. University of Oxford (United Kingdom)
  6. Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
  7. Duke University, Durham, NC (United States)
  8. University of Cape Town (South Africa); Centre for High Performance Computing (CHPR), Cape Town (South Africa); National University of Ireland Galway (Ireland)
+ Show Author Affiliations

The pattern of viral diversification in newly infected individuals provides information about the host environment and immune responses typically experienced by the newly transmitted virus. For example, sites that tend to evolve rapidly across multiple early-infection patients could be involved in enabling escape from common early immune responses, could represent adaptation for rapid growth in a newly infected host, or could represent reversion from less fit forms of the virus that were selected for immune escape in previous hosts. Here we investigated the diversification of HIV-1 env coding sequences in 81 very early B subtype infections previously shown to have resulted from transmission or expansion of single viruses (n = 78) or two closely related viruses (n = 3). In these cases, the sequence of the infecting virus can be estimated accurately, enabling inference of both the direction of substitutions as well as distinction between insertion and deletion events. By integrating information across multiple acutely infected hosts, we find evidence of adaptive evolution of HIV-1 env and identify a subset of codon sites that diversified more rapidly than can be explained by a model of neutral evolution. Of 24 such rapidly diversifying sites, 14 were either i) clustered and embedded in CTL epitopes that were verified experimentally or predicted based on the individual’s HLA or ii) in a nucleotide context indicative of APOBEC-mediated G-to-A substitutions, despite having excluded heavily hypermutated sequences prior to the analysis. In several cases, a rapidly evolving site was embedded both in an APOBEC motif and in a CTL epitope, suggesting that APOBEC may facilitate early immune escape. Ten rapidly diversifying sites could not be explained by CTL escape or APOBEC hypermutation, including the most frequently mutated site, in the fusion peptide of gp41. We also examined the distribution, extent, and sequence context of insertions and deletions, and we provide evidence that the length variation seen in hypervariable loop regions of the envelope glycoprotein is a consequence of selection and not of mutational hotspots. Our results provide a detailed view of the process of diversification of HIV-1 following transmission, highlighting the role of CTL escape and hypermutation in shaping viral evolution during the establishment of new infections.

Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); Bill & Melinda Gates Foundation; UAB Center for AIDS Research
Grant/Contract Number:
AC52-06NA25396; AI67854; AI27767; 37874
OSTI ID:
1627892
Journal Information:
PLoS Pathogens, Vol. 5, Issue 5; ISSN 1553-7374
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

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text January 2008

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Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection journal June 2009
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Transmission of Single HIV-1 Genomes and Dynamics of Early Immune Escape Revealed by Ultra-Deep Sequencing journal August 2010
Natural Polymorphisms in Human APOBEC3H and HIV-1 Vif Combine in Primary T Lymphocytes to Affect Viral G-to-A Mutation Levels and Infectivity journal November 2014
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