Variable fitness impact of HIV-1 escape mutations to cytotoxic T lymphocyte (CTL) response.
Human lymphocyte antigen (HLA)-restricted CD8(+) cytotoxic T lymphocytes (CTL) target and kill HIV-infected cells expressing cognate viral epitopes. This response selects for escape mutations within CTL epitopes that can diminish viral replication fitness. Here, we assess the fitness impact of escap...
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2009
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oai:doaj.org-article:73d3c53637944733899bd6ed54aaad982021-11-25T05:47:08ZVariable fitness impact of HIV-1 escape mutations to cytotoxic T lymphocyte (CTL) response.1553-73661553-737410.1371/journal.ppat.1000365https://doaj.org/article/73d3c53637944733899bd6ed54aaad982009-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19343217/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Human lymphocyte antigen (HLA)-restricted CD8(+) cytotoxic T lymphocytes (CTL) target and kill HIV-infected cells expressing cognate viral epitopes. This response selects for escape mutations within CTL epitopes that can diminish viral replication fitness. Here, we assess the fitness impact of escape mutations emerging in seven CTL epitopes in the gp120 Env and p24 Gag coding regions of an individual followed longitudinally from the time of acute HIV-1 infection, as well as some of these same epitopes recognized in other HIV-1-infected individuals. Nine dominant mutations appeared in five gp120 epitopes within the first year of infection, whereas all four mutations found in two p24 epitopes emerged after nearly two years of infection. These mutations were introduced individually into the autologous gene found in acute infection and then placed into a full-length, infectious viral genome. When competed against virus expressing the parental protein, fitness loss was observed with only one of the nine gp120 mutations, whereas four had no effect and three conferred a slight increase in fitness. In contrast, mutations conferring CTL escape in the p24 epitopes significantly decreased viral fitness. One particular escape mutation within a p24 epitope was associated with reduced peptide recognition and high viral fitness costs but was replaced by a fitness-neutral mutation. This mutation appeared to alter epitope processing concomitant with a reduced CTL response. In conclusion, CTL escape mutations in HIV-1 Gag p24 were associated with significant fitness costs, whereas most escape mutations in the Env gene were fitness neutral, suggesting a balance between immunologic escape and replicative fitness costs.Ryan M TroyerJohn McNevinYi LiuShao Chong ZhangRandall W KrizanAwet AbrahaDenis M TebitHong ZhaoSantiago AvilaMichael A LobritzM Juliana McElrathSylvie Le GallJames I MullinsEric J ArtsPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 5, Iss 4, p e1000365 (2009) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Ryan M Troyer John McNevin Yi Liu Shao Chong Zhang Randall W Krizan Awet Abraha Denis M Tebit Hong Zhao Santiago Avila Michael A Lobritz M Juliana McElrath Sylvie Le Gall James I Mullins Eric J Arts Variable fitness impact of HIV-1 escape mutations to cytotoxic T lymphocyte (CTL) response. |
| description |
Human lymphocyte antigen (HLA)-restricted CD8(+) cytotoxic T lymphocytes (CTL) target and kill HIV-infected cells expressing cognate viral epitopes. This response selects for escape mutations within CTL epitopes that can diminish viral replication fitness. Here, we assess the fitness impact of escape mutations emerging in seven CTL epitopes in the gp120 Env and p24 Gag coding regions of an individual followed longitudinally from the time of acute HIV-1 infection, as well as some of these same epitopes recognized in other HIV-1-infected individuals. Nine dominant mutations appeared in five gp120 epitopes within the first year of infection, whereas all four mutations found in two p24 epitopes emerged after nearly two years of infection. These mutations were introduced individually into the autologous gene found in acute infection and then placed into a full-length, infectious viral genome. When competed against virus expressing the parental protein, fitness loss was observed with only one of the nine gp120 mutations, whereas four had no effect and three conferred a slight increase in fitness. In contrast, mutations conferring CTL escape in the p24 epitopes significantly decreased viral fitness. One particular escape mutation within a p24 epitope was associated with reduced peptide recognition and high viral fitness costs but was replaced by a fitness-neutral mutation. This mutation appeared to alter epitope processing concomitant with a reduced CTL response. In conclusion, CTL escape mutations in HIV-1 Gag p24 were associated with significant fitness costs, whereas most escape mutations in the Env gene were fitness neutral, suggesting a balance between immunologic escape and replicative fitness costs. |
| format |
article |
| author |
Ryan M Troyer John McNevin Yi Liu Shao Chong Zhang Randall W Krizan Awet Abraha Denis M Tebit Hong Zhao Santiago Avila Michael A Lobritz M Juliana McElrath Sylvie Le Gall James I Mullins Eric J Arts |
| author_facet |
Ryan M Troyer John McNevin Yi Liu Shao Chong Zhang Randall W Krizan Awet Abraha Denis M Tebit Hong Zhao Santiago Avila Michael A Lobritz M Juliana McElrath Sylvie Le Gall James I Mullins Eric J Arts |
| author_sort |
Ryan M Troyer |
| title |
Variable fitness impact of HIV-1 escape mutations to cytotoxic T lymphocyte (CTL) response. |
| title_short |
Variable fitness impact of HIV-1 escape mutations to cytotoxic T lymphocyte (CTL) response. |
| title_full |
Variable fitness impact of HIV-1 escape mutations to cytotoxic T lymphocyte (CTL) response. |
| title_fullStr |
Variable fitness impact of HIV-1 escape mutations to cytotoxic T lymphocyte (CTL) response. |
| title_full_unstemmed |
Variable fitness impact of HIV-1 escape mutations to cytotoxic T lymphocyte (CTL) response. |
| title_sort |
variable fitness impact of hiv-1 escape mutations to cytotoxic t lymphocyte (ctl) response. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2009 |
| url |
https://doaj.org/article/73d3c53637944733899bd6ed54aaad98 |
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