CTL escape mediated by proteasomal destruction of an HIV-1 cryptic epitope.
Cytotoxic CD8+ T cells (CTLs) play a critical role in controlling viral infections. HIV-infected individuals develop CTL responses against epitopes derived from viral proteins, but also against cryptic epitopes encoded by viral alternative reading frames (ARF). We studied here the mechanisms of HIV-...
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2011
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oai:doaj.org-article:11741e79371a421faecf68c1ab9f787a2021-11-18T06:03:24ZCTL escape mediated by proteasomal destruction of an HIV-1 cryptic epitope.1553-73661553-737410.1371/journal.ppat.1002049https://doaj.org/article/11741e79371a421faecf68c1ab9f787a2011-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21589903/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Cytotoxic CD8+ T cells (CTLs) play a critical role in controlling viral infections. HIV-infected individuals develop CTL responses against epitopes derived from viral proteins, but also against cryptic epitopes encoded by viral alternative reading frames (ARF). We studied here the mechanisms of HIV-1 escape from CTLs targeting one such cryptic epitope, Q9VF, encoded by an HIVgag ARF and presented by HLA-B*07. Using PBMCs of HIV-infected patients, we first cloned and sequenced proviral DNA encoding for Q9VF. We identified several polymorphisms with a minority of proviruses encoding at position 5 an aspartic acid (Q9VF/5D) and a majority encoding an asparagine (Q9VF/5N). We compared the prevalence of each variant in PBMCs of HLA-B*07+ and HLA-B*07- patients. Proviruses encoding Q9VF/5D were significantly less represented in HLA-B*07+ than in HLA-B*07- patients, suggesting that Q9FV/5D encoding viruses might be under selective pressure in HLA-B*07+ individuals. We thus analyzed ex vivo CTL responses directed against Q9VF/5D and Q9VF/5N. Around 16% of HLA-B*07+ patients exhibited CTL responses targeting Q9VF epitopes. The frequency and the magnitude of CTL responses induced with Q9VF/5D or Q9VF/5N peptides were almost equal indicating a possible cross-reactivity of the same CTLs on the two peptides. We then dissected the cellular mechanisms involved in the presentation of Q9VF variants. As expected, cells infected with HIV strains encoding for Q9VF/5D were recognized by Q9VF/5D-specific CTLs. In contrast, Q9VF/5N-encoding strains were neither recognized by Q9VF/5N- nor by Q9VF/5D-specific CTLs. Using in vitro proteasomal digestions and MS/MS analysis, we demonstrate that the 5N variation introduces a strong proteasomal cleavage site within the epitope, leading to a dramatic reduction of Q9VF epitope production. Our results strongly suggest that HIV-1 escapes CTL surveillance by introducing mutations leading to HIV ARF-epitope destruction by proteasomes.Sylvain CardinaudGesa ConsiglieriRomain BouziatAlejandra UrrutiaStéphanie Graff-DuboisSlim FouratiIsabelle MaletJulien GuergnonAmélie GuihotChristine KatlamaBrigitte AutranPeter van EndertFrançois A LemonnierVictor AppayOlivier SchwartzPeter M KloetzelArnaud MorisPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 7, Iss 5, p e1002049 (2011) |
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DOAJ |
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Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Sylvain Cardinaud Gesa Consiglieri Romain Bouziat Alejandra Urrutia Stéphanie Graff-Dubois Slim Fourati Isabelle Malet Julien Guergnon Amélie Guihot Christine Katlama Brigitte Autran Peter van Endert François A Lemonnier Victor Appay Olivier Schwartz Peter M Kloetzel Arnaud Moris CTL escape mediated by proteasomal destruction of an HIV-1 cryptic epitope. |
| description |
Cytotoxic CD8+ T cells (CTLs) play a critical role in controlling viral infections. HIV-infected individuals develop CTL responses against epitopes derived from viral proteins, but also against cryptic epitopes encoded by viral alternative reading frames (ARF). We studied here the mechanisms of HIV-1 escape from CTLs targeting one such cryptic epitope, Q9VF, encoded by an HIVgag ARF and presented by HLA-B*07. Using PBMCs of HIV-infected patients, we first cloned and sequenced proviral DNA encoding for Q9VF. We identified several polymorphisms with a minority of proviruses encoding at position 5 an aspartic acid (Q9VF/5D) and a majority encoding an asparagine (Q9VF/5N). We compared the prevalence of each variant in PBMCs of HLA-B*07+ and HLA-B*07- patients. Proviruses encoding Q9VF/5D were significantly less represented in HLA-B*07+ than in HLA-B*07- patients, suggesting that Q9FV/5D encoding viruses might be under selective pressure in HLA-B*07+ individuals. We thus analyzed ex vivo CTL responses directed against Q9VF/5D and Q9VF/5N. Around 16% of HLA-B*07+ patients exhibited CTL responses targeting Q9VF epitopes. The frequency and the magnitude of CTL responses induced with Q9VF/5D or Q9VF/5N peptides were almost equal indicating a possible cross-reactivity of the same CTLs on the two peptides. We then dissected the cellular mechanisms involved in the presentation of Q9VF variants. As expected, cells infected with HIV strains encoding for Q9VF/5D were recognized by Q9VF/5D-specific CTLs. In contrast, Q9VF/5N-encoding strains were neither recognized by Q9VF/5N- nor by Q9VF/5D-specific CTLs. Using in vitro proteasomal digestions and MS/MS analysis, we demonstrate that the 5N variation introduces a strong proteasomal cleavage site within the epitope, leading to a dramatic reduction of Q9VF epitope production. Our results strongly suggest that HIV-1 escapes CTL surveillance by introducing mutations leading to HIV ARF-epitope destruction by proteasomes. |
| format |
article |
| author |
Sylvain Cardinaud Gesa Consiglieri Romain Bouziat Alejandra Urrutia Stéphanie Graff-Dubois Slim Fourati Isabelle Malet Julien Guergnon Amélie Guihot Christine Katlama Brigitte Autran Peter van Endert François A Lemonnier Victor Appay Olivier Schwartz Peter M Kloetzel Arnaud Moris |
| author_facet |
Sylvain Cardinaud Gesa Consiglieri Romain Bouziat Alejandra Urrutia Stéphanie Graff-Dubois Slim Fourati Isabelle Malet Julien Guergnon Amélie Guihot Christine Katlama Brigitte Autran Peter van Endert François A Lemonnier Victor Appay Olivier Schwartz Peter M Kloetzel Arnaud Moris |
| author_sort |
Sylvain Cardinaud |
| title |
CTL escape mediated by proteasomal destruction of an HIV-1 cryptic epitope. |
| title_short |
CTL escape mediated by proteasomal destruction of an HIV-1 cryptic epitope. |
| title_full |
CTL escape mediated by proteasomal destruction of an HIV-1 cryptic epitope. |
| title_fullStr |
CTL escape mediated by proteasomal destruction of an HIV-1 cryptic epitope. |
| title_full_unstemmed |
CTL escape mediated by proteasomal destruction of an HIV-1 cryptic epitope. |
| title_sort |
ctl escape mediated by proteasomal destruction of an hiv-1 cryptic epitope. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2011 |
| url |
https://doaj.org/article/11741e79371a421faecf68c1ab9f787a |
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