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Title: A strongly selected mutation in the HIV-1 genome is independent of T cell responses and neutralizing antibodies

Mutations rapidly accumulate in the HIV-1 genome after infection. Some of those mutations are selected by host immune responses and often cause viral fitness losses. This study is to investigate whether strongly selected mutations that are not associated with immune responses result in fitness losses. Strongly selected mutations were identified by analyzing 5'-half HIV-1 genome (gag/pol) sequences from longitudinal samples of subject CH0131. The K43R mutation in the gag gene was first detected at day 91 post screening and was fixed in the viral population at day 273 while the synonymous N323tc mutation was first detected at day 177 and fixed at day 670. No conventional or cryptic T cell responses were detected against either mutation sites by ELISpot analysis. However, when fitness costs of both mutations were measured by introducing each mutation into their cognate transmitted/founder (T/F) viral genome, the K43R mutation caused a significant fitness loss while the N323tc mutation had little impact on viral fitness. In conclusion, the rapid fixation, the lack of detectable immune responses and the significant fitness cost of the K43R mutation suggests that it was strongly selected by host factors other than T cell responses and neutralizing antibodies.
Authors:
 [1] ;  [1] ;  [2] ;  [1] ;  [3] ;  [4] ;  [5] ;  [5] ;  [4] ;  [6] ;  [6] ; ORCiD logo [1]
  1. Jilin Univ., Changchun (China). National Engineering Lab. for AIDS Vaccine, School of Life Sciences; Duke Univ., Durham, NC (United States). Medical Center, Duke Human Vaccine Inst., Dept. of Medicine
  2. Duke Univ., Durham, NC (United States). Medical Center, Duke Human Vaccine Inst., Dept. of Medicine
  3. Univ. of North Carolina, Chapel Hill, NC (United States). Dept. of Microbiology, Immunology and Medicine
  4. Univ. of Oxford (United Kingdom). Weatherall Inst. of Molecular Medicine
  5. Duke Univ., Durham, NC (United States). Medical Center, Dept. of Surgery
  6. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Division
Publication Date:
Report Number(s):
LA-UR-17-21998
Journal ID: ISSN 1742-4690
Grant/Contract Number:
AC52-06NA25396; 31670162; AI067854; AI100645; AI028433; OD011095
Type:
Accepted Manuscript
Journal Name:
Retrovirology
Additional Journal Information:
Journal Volume: 14; Journal Issue: 1; Journal ID: ISSN 1742-4690
Publisher:
BioMed Central
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org:
National Institutes of Health (NIH); National Natural Science Foundation of China (NNSFC); USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biological Science; Mutation; Selection; Immune responses; Cryptic T cell response; Fitness; Escape
OSTI Identifier:
1418764

Liu, Donglai, Wang, Chu, Hora, Bhavna, Zuo, Tao, Goonetilleke, Nilu, Liu, Michael K. P., Berrong, Mark, Ferrari, Guido, McMichael, Andrew J., Bhattacharya, Tanmoy, Perelson, Alan S., and Gao, Feng. A strongly selected mutation in the HIV-1 genome is independent of T cell responses and neutralizing antibodies. United States: N. p., Web. doi:10.1186/s12977-017-0371-4.
Liu, Donglai, Wang, Chu, Hora, Bhavna, Zuo, Tao, Goonetilleke, Nilu, Liu, Michael K. P., Berrong, Mark, Ferrari, Guido, McMichael, Andrew J., Bhattacharya, Tanmoy, Perelson, Alan S., & Gao, Feng. A strongly selected mutation in the HIV-1 genome is independent of T cell responses and neutralizing antibodies. United States. doi:10.1186/s12977-017-0371-4.
Liu, Donglai, Wang, Chu, Hora, Bhavna, Zuo, Tao, Goonetilleke, Nilu, Liu, Michael K. P., Berrong, Mark, Ferrari, Guido, McMichael, Andrew J., Bhattacharya, Tanmoy, Perelson, Alan S., and Gao, Feng. 2017. "A strongly selected mutation in the HIV-1 genome is independent of T cell responses and neutralizing antibodies". United States. doi:10.1186/s12977-017-0371-4. https://www.osti.gov/servlets/purl/1418764.
@article{osti_1418764,
title = {A strongly selected mutation in the HIV-1 genome is independent of T cell responses and neutralizing antibodies},
author = {Liu, Donglai and Wang, Chu and Hora, Bhavna and Zuo, Tao and Goonetilleke, Nilu and Liu, Michael K. P. and Berrong, Mark and Ferrari, Guido and McMichael, Andrew J. and Bhattacharya, Tanmoy and Perelson, Alan S. and Gao, Feng},
abstractNote = {Mutations rapidly accumulate in the HIV-1 genome after infection. Some of those mutations are selected by host immune responses and often cause viral fitness losses. This study is to investigate whether strongly selected mutations that are not associated with immune responses result in fitness losses. Strongly selected mutations were identified by analyzing 5'-half HIV-1 genome (gag/pol) sequences from longitudinal samples of subject CH0131. The K43R mutation in the gag gene was first detected at day 91 post screening and was fixed in the viral population at day 273 while the synonymous N323tc mutation was first detected at day 177 and fixed at day 670. No conventional or cryptic T cell responses were detected against either mutation sites by ELISpot analysis. However, when fitness costs of both mutations were measured by introducing each mutation into their cognate transmitted/founder (T/F) viral genome, the K43R mutation caused a significant fitness loss while the N323tc mutation had little impact on viral fitness. In conclusion, the rapid fixation, the lack of detectable immune responses and the significant fitness cost of the K43R mutation suggests that it was strongly selected by host factors other than T cell responses and neutralizing antibodies.},
doi = {10.1186/s12977-017-0371-4},
journal = {Retrovirology},
number = 1,
volume = 14,
place = {United States},
year = {2017},
month = {10}
}

Works referenced in this record:

Determinants of Human Immunodeficiency Virus Type 1 Escape from the Primary CD8+ Cytotoxic T Lymphocyte Response
journal, November 2004
  • Jones, Nicola A.; Wei, Xiping; Flower, Darren R.
  • The Journal of Experimental Medicine, Vol. 200, Issue 10, p. 1243-1256
  • DOI: 10.1084/jem.20040511