Extreme genetic fragility of the HIV-1 capsid.
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) do...
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2013
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oai:doaj.org-article:34a40bd4ec5d4f0b983759833986b91d2021-11-18T06:05:29ZExtreme genetic fragility of the HIV-1 capsid.1553-73661553-737410.1371/journal.ppat.1003461https://doaj.org/article/34a40bd4ec5d4f0b983759833986b91d2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23818857/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Genetic 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.Suzannah J RihnSam J WilsonNick J LomanMudathir AlimSaskia E BakkerDavid BhellaRobert J GiffordFrazer J RixonPaul D BieniaszPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 6, p e1003461 (2013) |
| institution |
DOAJ |
| collection |
DOAJ |
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| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Suzannah J Rihn Sam J Wilson Nick J Loman Mudathir Alim Saskia E Bakker David Bhella Robert J Gifford Frazer J Rixon Paul D Bieniasz Extreme genetic fragility of the HIV-1 capsid. |
| description |
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. |
| format |
article |
| author |
Suzannah J Rihn Sam J Wilson Nick J Loman Mudathir Alim Saskia E Bakker David Bhella Robert J Gifford Frazer J Rixon Paul D Bieniasz |
| author_facet |
Suzannah J Rihn Sam J Wilson Nick J Loman Mudathir Alim Saskia E Bakker David Bhella Robert J Gifford Frazer J Rixon Paul D Bieniasz |
| author_sort |
Suzannah J Rihn |
| title |
Extreme genetic fragility of the HIV-1 capsid. |
| title_short |
Extreme genetic fragility of the HIV-1 capsid. |
| title_full |
Extreme genetic fragility of the HIV-1 capsid. |
| title_fullStr |
Extreme genetic fragility of the HIV-1 capsid. |
| title_full_unstemmed |
Extreme genetic fragility of the HIV-1 capsid. |
| title_sort |
extreme genetic fragility of the hiv-1 capsid. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/34a40bd4ec5d4f0b983759833986b91d |
| work_keys_str_mv |
AT suzannahjrihn extremegeneticfragilityofthehiv1capsid AT samjwilson extremegeneticfragilityofthehiv1capsid AT nickjloman extremegeneticfragilityofthehiv1capsid AT mudathiralim extremegeneticfragilityofthehiv1capsid AT saskiaebakker extremegeneticfragilityofthehiv1capsid AT davidbhella extremegeneticfragilityofthehiv1capsid AT robertjgifford extremegeneticfragilityofthehiv1capsid AT frazerjrixon extremegeneticfragilityofthehiv1capsid AT pauldbieniasz extremegeneticfragilityofthehiv1capsid |
| _version_ |
1718424595007012864 |