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Title: Recombination enhances HIV-1 envelope diversity by facilitating the survival of latent genomic fragments in the plasma virus population

HIV-1 is subject to immune pressure exerted by the host, giving variants that escape the immune response an advantage. Virus released from activated latent cells competes against variants that have continually evolved and adapted to host immune pressure. Nevertheless, there is increasing evidence that virus displaying a signal of latency survives in patient plasma despite having reduced fitness due to long-term immune memory. We investigated the survival of virus with latent envelope genomic fragments by simulating within-host HIV-1 sequence evolution and the cycling of viral lineages in and out of the latent reservoir. Our model incorporates a detailed mutation process including nucleotide substitution, recombination, latent reservoir dynamics, diversifying selection pressure driven by the immune response, and purifying selection pressure asserted by deleterious mutations. We evaluated the ability of our model to capture sequence evolution in vivo by comparing our simulated sequences to HIV-1 envelope sequence data from 16 HIV-infected untreated patients. Empirical sequence divergence and diversity measures were qualitatively and quantitatively similar to those of our simulated HIV-1 populations, suggesting that our model invokes realistic trends of HIV-1 genetic evolution. Moreover, reconstructed phylogenies of simulated and patient HIV-1 populations showed similar topological structures. Our simulation results suggest that recombination ismore » a key mechanism facilitating the persistence of virus with latent envelope genomic fragments in the productively infected cell population. Recombination increased the survival probability of latent virus forms approximately 13-fold. Prevalence of virus with latent fragments in productively infected cells was observed in only 2% of simulations when we ignored recombination, while the proportion increased to 27% of simulations when we allowed recombination. We also found that the selection pressures exerted by different fitness landscapes influenced the shape of phylogenies, diversity trends, and survival of virus with latent genomic fragments. Furthermore, our model predicts that the persistence of latent genomic fragments from multiple different ancestral origins increases sequence diversity in plasma for reasonable fitness landscapes.« less
Authors:
 [1] ;  [2] ;  [1] ;  [1] ;  [1] ;  [3]
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  2. The Pennsylvania State Univ., University Park, PA (United States)
  3. Univ. of Zurich (Switzerland)
Publication Date:
OSTI Identifier:
1235898
Report Number(s):
LA-UR--15-21253
Journal ID: ISSN 1553-7358
Grant/Contract Number:
AC52-06NA25396
Type:
Accepted Manuscript
Journal Name:
PLoS Computational Biology (Online)
Additional Journal Information:
Journal Name: PLoS Computational Biology (Online); Journal Volume: 11; Journal Issue: 12; Journal ID: ISSN 1553-7358
Publisher:
Public Library of Science
Research Org:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 97 MATHEMATICS AND COMPUTING HIV-1; immune response; viral genomics; viral persistence and latency; viral evolution; viral replication; evolutionary immunology; phylogenetics