Reversion and T Cell Escape Mutations Compensate the Fitness Loss of a CD8+ T Cell Escape Mutant in Their Cognate Transmitted/Founder Virus
Abstract
Immune escape mutations that revert back to the consensus sequence frequently occur in newly HIV-1-infected individuals and have been thought to render the viruses more fit. However, their impact on viral fitness and their interaction with other immune escape mutations have not been evaluated in the background of their cognate transmitted/founder (T/F) viral genomes. To precisely determine the role of reversion mutations, we introduced reversion mutations alone or together with CD8+ T cell escape mutations in their unmodified cognate T/F viral genome and determined their impact on viral fitness in primary CD4+ T cells. Two reversion mutations, V247I and I64T, were identified in Gag and Tat, respectively, but neither had measurable effect on the fitness of their cognate T/F virus. The V247I and G248A mutations that were detected before and concurrently with the potent T cell escape mutation T242N, respectively, were selected by early T cell responses. The V247I or the G248A mutation alone partially restored the fitness loss caused by the T242N mutation. Together they could fully restore the fitness of the T242N mutant to the T/F level. These results demonstrate that the fitness loss caused by a T cell escape mutation could be compensated by preexisting or concurrentmore »
- Authors:
-
- Duke Univ., Durham, NC (United States). Medical Center. Duke Human Vaccine Inst.
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Div.; Santa Fe Inst. (SFI), Santa Fe, NM (United States)
- Univ. of Oxford (United Kingdom). Weatherall Inst. of Molecular Medicine
- Univ. of Pennsylvania, Philadelphia, PA (United States). Depts. of Medicine and Microbiology
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Div.
- Publication Date:
- Research Org.:
- Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1627718
- Grant/Contract Number:
- AC52-06NA25396
- Resource Type:
- Accepted Manuscript
- Journal Name:
- PLoS ONE
- Additional Journal Information:
- Journal Volume: 9; Journal Issue: 7; Journal ID: ISSN 1932-6203
- Publisher:
- Public Library of Science
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Science & Technology - Other Topics
Citation Formats
Song, Hongshuo, Hora, Bhavna, Bhattacharya, Tanmoy, Goonetilleke, Nilu, Liu, Michael K. P., Wiehe, Kevin, Li, Hui, Iyer, Shilpa S., McMichael, Andrew J., Perelson, Alan S., and Gao, Feng. Reversion and T Cell Escape Mutations Compensate the Fitness Loss of a CD8+ T Cell Escape Mutant in Their Cognate Transmitted/Founder Virus. United States: N. p., 2014.
Web. doi:10.1371/journal.pone.0102734.
Song, Hongshuo, Hora, Bhavna, Bhattacharya, Tanmoy, Goonetilleke, Nilu, Liu, Michael K. P., Wiehe, Kevin, Li, Hui, Iyer, Shilpa S., McMichael, Andrew J., Perelson, Alan S., & Gao, Feng. Reversion and T Cell Escape Mutations Compensate the Fitness Loss of a CD8+ T Cell Escape Mutant in Their Cognate Transmitted/Founder Virus. United States. https://doi.org/10.1371/journal.pone.0102734
Song, Hongshuo, Hora, Bhavna, Bhattacharya, Tanmoy, Goonetilleke, Nilu, Liu, Michael K. P., Wiehe, Kevin, Li, Hui, Iyer, Shilpa S., McMichael, Andrew J., Perelson, Alan S., and Gao, Feng. Wed .
"Reversion and T Cell Escape Mutations Compensate the Fitness Loss of a CD8+ T Cell Escape Mutant in Their Cognate Transmitted/Founder Virus". United States. https://doi.org/10.1371/journal.pone.0102734. https://www.osti.gov/servlets/purl/1627718.
@article{osti_1627718,
title = {Reversion and T Cell Escape Mutations Compensate the Fitness Loss of a CD8+ T Cell Escape Mutant in Their Cognate Transmitted/Founder Virus},
author = {Song, Hongshuo and Hora, Bhavna and Bhattacharya, Tanmoy and Goonetilleke, Nilu and Liu, Michael K. P. and Wiehe, Kevin and Li, Hui and Iyer, Shilpa S. and McMichael, Andrew J. and Perelson, Alan S. and Gao, Feng},
abstractNote = {Immune escape mutations that revert back to the consensus sequence frequently occur in newly HIV-1-infected individuals and have been thought to render the viruses more fit. However, their impact on viral fitness and their interaction with other immune escape mutations have not been evaluated in the background of their cognate transmitted/founder (T/F) viral genomes. To precisely determine the role of reversion mutations, we introduced reversion mutations alone or together with CD8+ T cell escape mutations in their unmodified cognate T/F viral genome and determined their impact on viral fitness in primary CD4+ T cells. Two reversion mutations, V247I and I64T, were identified in Gag and Tat, respectively, but neither had measurable effect on the fitness of their cognate T/F virus. The V247I and G248A mutations that were detected before and concurrently with the potent T cell escape mutation T242N, respectively, were selected by early T cell responses. The V247I or the G248A mutation alone partially restored the fitness loss caused by the T242N mutation. Together they could fully restore the fitness of the T242N mutant to the T/F level. These results demonstrate that the fitness loss caused by a T cell escape mutation could be compensated by preexisting or concurrent reversion and other T cell escape mutations. Our findings indicate that the overall viral fitness is modulated by the complex interplay among T cell escape, compensatory and reversion mutations to maintain the balance between immune escape and viral replication capacity.},
doi = {10.1371/journal.pone.0102734},
journal = {PLoS ONE},
number = 7,
volume = 9,
place = {United States},
year = {Wed Jul 16 00:00:00 EDT 2014},
month = {Wed Jul 16 00:00:00 EDT 2014}
}
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