Extreme genetic fragility of the HIV-1 capsid

Rihn, S.J. , Wilson, S.J. , Loman, N.J., Alim, M., Bakker, S.E., Bhella, D. , Gifford, R.J., Rixon, F.J. and Bieniasz, P.D. (2013) Extreme genetic fragility of the HIV-1 capsid. PLoS Pathogens, 9(6), e1003461. (doi:10.1371/journal.ppat.1003461) (PMID:23818857) (PMCID:PMC3688543)

Rihn, S.J. , Wilson, S.J. , Loman, N.J., Alim, M., Bakker, S.E., Bhella, D. , Gifford, R.J., Rixon, F.J. and Bieniasz, P.D. (2013) Extreme genetic fragility of the HIV-1 capsid. PLoS Pathogens, 9(6), e1003461. (doi:10.1371/journal.ppat.1003461) (PMID:23818857) (PMCID:PMC3688543)

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Abstract

Genetic robustness, or fragility, is defined as the ability, or lack thereof, of a biological entity to maintain function in the face of mutations. Viruses that replicate via RNA intermediates exhibit high mutation rates, and robustness should be particularly advantageous to them. The capsid (CA) domain of the HIV-1 Gag protein is under strong pressure to conserve functional roles in viral assembly, maturation, uncoating, and nuclear import. However, CA is also under strong immunological pressure to diversify. Therefore, it would be particularly advantageous for CA to evolve genetic robustness. To measure the genetic robustness of HIV-1 CA, we generated a library of single amino acid substitution mutants, encompassing almost half the residues in CA. Strikingly, we found HIV-1 CA to be the most genetically fragile protein that has been analyzed using such an approach, with 70% of mutations yielding replication-defective viruses. Although CA participates in several steps in HIV-1 replication, analysis of conditionally (temperature sensitive) and constitutively non-viable mutants revealed that the biological basis for its genetic fragility was primarily the need to coordinate the accurate and efficient assembly of mature virions. All mutations that exist in naturally occurring HIV-1 subtype B populations at a frequency >3%, and were also present in the mutant library, had fitness levels that were >40% of WT. However, a substantial fraction of mutations with high fitness did not occur in natural populations, suggesting another form of selection pressure limiting variation in vivo. Additionally, known protective CTL epitopes occurred preferentially in domains of the HIV-1 CA that were even more genetically fragile than HIV-1 CA as a whole. The extreme genetic fragility of HIV-1 CA may be one reason why cell-mediated immune responses to Gag correlate with better prognosis in HIV-1 infection, and suggests that CA is a good target for therapy and vaccination strategies.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Gifford, Dr Robert and Bhella, Professor David and Rihn, Dr Suzannah and Rixon, Dr Frazer and Bakker, Dr Saskia and Wilson, Dr Sam
Authors: Rihn, S.J., Wilson, S.J., Loman, N.J., Alim, M., Bakker, S.E., Bhella, D., Gifford, R.J., Rixon, F.J., and Bieniasz, P.D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7366
ISSN (Online):1553-7366
Copyright Holders:Copyright © 2013 The Authors
First Published:First published in PLoS Pathogens 9(6):e1003461
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656541Structural studies of human viruses and host interactionsDavid BhellaMedical Research Council (MRC)MC_UU_12014/7MVLS III - CENTRE FOR VIRUS RESEARCH
501441Centre for Integrated VirologyMassimo PalmariniMedical Research Council (MRC)G0801822MVLS III - CENTRE FOR VIRUS RESEARCH
656531Structural studies on human virusesFrazer RixonMedical Research Council (MRC)MC_UU_12014/6MVLS III - CENTRE FOR VIRUS RESEARCH