Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa.
<h4>Background</h4>Viruses can evade immune surveillance, but the underlying mechanisms are insufficiently understood. Here, we sought to understand the mechanisms by which natural killer (NK) cells recognize HIV-1-infected cells and how this virus can evade NK-cell-mediated immune press...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-11-01
|
| Series: | PLoS Medicine |
| Online Access: | https://doi.org/10.1371/journal.pmed.1001900 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849469981070196736 |
|---|---|
| author | Angelique Hölzemer Christina F Thobakgale Camilo A Jimenez Cruz Wilfredo F Garcia-Beltran Jonathan M Carlson Nienke H van Teijlingen Jaclyn K Mann Manjeetha Jaggernath Seung-gu Kang Christian Körner Amy W Chung Jamie L Schafer David T Evans Galit Alter Bruce D Walker Philip J Goulder Mary Carrington Pia Hartmann Thomas Pertel Ruhong Zhou Thumbi Ndung'u Marcus Altfeld |
| author_facet | Angelique Hölzemer Christina F Thobakgale Camilo A Jimenez Cruz Wilfredo F Garcia-Beltran Jonathan M Carlson Nienke H van Teijlingen Jaclyn K Mann Manjeetha Jaggernath Seung-gu Kang Christian Körner Amy W Chung Jamie L Schafer David T Evans Galit Alter Bruce D Walker Philip J Goulder Mary Carrington Pia Hartmann Thomas Pertel Ruhong Zhou Thumbi Ndung'u Marcus Altfeld |
| author_sort | Angelique Hölzemer |
| collection | DOAJ |
| description | <h4>Background</h4>Viruses can evade immune surveillance, but the underlying mechanisms are insufficiently understood. Here, we sought to understand the mechanisms by which natural killer (NK) cells recognize HIV-1-infected cells and how this virus can evade NK-cell-mediated immune pressure.<h4>Methods and findings</h4>Two sequence mutations in p24 Gag associated with the presence of specific KIR/HLA combined genotypes were identified in HIV-1 clade C viruses from a large cohort of infected, untreated individuals in South Africa (n = 392), suggesting viral escape from KIR+ NK cells through sequence variations within HLA class I-presented epitopes. One sequence polymorphism at position 303 of p24 Gag (TGag303V), selected for in infected individuals with both KIR2DL3 and HLA-C*03:04, enabled significantly better binding of the inhibitory KIR2DL3 receptor to HLA-C*03:04-expressing cells presenting this variant epitope compared to the wild-type epitope (wild-type mean 18.01 ± 10.45 standard deviation [SD] and variant mean 44.67 ± 14.42 SD, p = 0.002). Furthermore, activation of primary KIR2DL3+ NK cells from healthy donors in response to HLA-C*03:04+ target cells presenting the variant epitope was significantly reduced in comparison to cells presenting the wild-type sequence (wild-type mean 0.78 ± 0.07 standard error of the mean [SEM] and variant mean 0.63 ± 0.07 SEM, p = 0.012). Structural modeling and surface plasmon resonance of KIR/peptide/HLA interactions in the context of the different viral sequence variants studied supported these results. Future studies will be needed to assess processing and antigen presentation of the investigated HIV-1 epitope in natural infection, and the consequences for viral control.<h4>Conclusions</h4>These data provide novel insights into how viruses can evade NK cell immunity through the selection of mutations in HLA-presented epitopes that enhance binding to inhibitory NK cell receptors. Better understanding of the mechanisms by which HIV-1 evades NK-cell-mediated immune pressure and the functional validation of a structural modeling approach will facilitate the development of novel targeted immune interventions to harness the antiviral activities of NK cells. |
| format | Article |
| id | doaj-art-fa6dc56a9531426d9574a273ad87bc21 |
| institution | Kabale University |
| issn | 1549-1277 1549-1676 |
| language | English |
| publishDate | 2015-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Medicine |
| spelling | doaj-art-fa6dc56a9531426d9574a273ad87bc212025-08-20T03:25:16ZengPublic Library of Science (PLoS)PLoS Medicine1549-12771549-16762015-11-011211e1001900; discussion e100190010.1371/journal.pmed.1001900Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa.Angelique HölzemerChristina F ThobakgaleCamilo A Jimenez CruzWilfredo F Garcia-BeltranJonathan M CarlsonNienke H van TeijlingenJaclyn K MannManjeetha JaggernathSeung-gu KangChristian KörnerAmy W ChungJamie L SchaferDavid T EvansGalit AlterBruce D WalkerPhilip J GoulderMary CarringtonPia HartmannThomas PertelRuhong ZhouThumbi Ndung'uMarcus Altfeld<h4>Background</h4>Viruses can evade immune surveillance, but the underlying mechanisms are insufficiently understood. Here, we sought to understand the mechanisms by which natural killer (NK) cells recognize HIV-1-infected cells and how this virus can evade NK-cell-mediated immune pressure.<h4>Methods and findings</h4>Two sequence mutations in p24 Gag associated with the presence of specific KIR/HLA combined genotypes were identified in HIV-1 clade C viruses from a large cohort of infected, untreated individuals in South Africa (n = 392), suggesting viral escape from KIR+ NK cells through sequence variations within HLA class I-presented epitopes. One sequence polymorphism at position 303 of p24 Gag (TGag303V), selected for in infected individuals with both KIR2DL3 and HLA-C*03:04, enabled significantly better binding of the inhibitory KIR2DL3 receptor to HLA-C*03:04-expressing cells presenting this variant epitope compared to the wild-type epitope (wild-type mean 18.01 ± 10.45 standard deviation [SD] and variant mean 44.67 ± 14.42 SD, p = 0.002). Furthermore, activation of primary KIR2DL3+ NK cells from healthy donors in response to HLA-C*03:04+ target cells presenting the variant epitope was significantly reduced in comparison to cells presenting the wild-type sequence (wild-type mean 0.78 ± 0.07 standard error of the mean [SEM] and variant mean 0.63 ± 0.07 SEM, p = 0.012). Structural modeling and surface plasmon resonance of KIR/peptide/HLA interactions in the context of the different viral sequence variants studied supported these results. Future studies will be needed to assess processing and antigen presentation of the investigated HIV-1 epitope in natural infection, and the consequences for viral control.<h4>Conclusions</h4>These data provide novel insights into how viruses can evade NK cell immunity through the selection of mutations in HLA-presented epitopes that enhance binding to inhibitory NK cell receptors. Better understanding of the mechanisms by which HIV-1 evades NK-cell-mediated immune pressure and the functional validation of a structural modeling approach will facilitate the development of novel targeted immune interventions to harness the antiviral activities of NK cells.https://doi.org/10.1371/journal.pmed.1001900 |
| spellingShingle | Angelique Hölzemer Christina F Thobakgale Camilo A Jimenez Cruz Wilfredo F Garcia-Beltran Jonathan M Carlson Nienke H van Teijlingen Jaclyn K Mann Manjeetha Jaggernath Seung-gu Kang Christian Körner Amy W Chung Jamie L Schafer David T Evans Galit Alter Bruce D Walker Philip J Goulder Mary Carrington Pia Hartmann Thomas Pertel Ruhong Zhou Thumbi Ndung'u Marcus Altfeld Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa. PLoS Medicine |
| title | Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa. |
| title_full | Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa. |
| title_fullStr | Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa. |
| title_full_unstemmed | Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa. |
| title_short | Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa. |
| title_sort | selection of an hla c 03 04 restricted hiv 1 p24 gag sequence variant is associated with viral escape from kir2dl3 natural killer cells data from an observational cohort in south africa |
| url | https://doi.org/10.1371/journal.pmed.1001900 |
| work_keys_str_mv | AT angeliqueholzemer selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT christinafthobakgale selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT camiloajimenezcruz selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT wilfredofgarciabeltran selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT jonathanmcarlson selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT nienkehvanteijlingen selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT jaclynkmann selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT manjeethajaggernath selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT seunggukang selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT christiankorner selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT amywchung selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT jamielschafer selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT davidtevans selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT galitalter selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT brucedwalker selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT philipjgoulder selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT marycarrington selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT piahartmann selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT thomaspertel selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT ruhongzhou selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT thumbindungu selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica AT marcusaltfeld selectionofanhlac0304restrictedhiv1p24gagsequencevariantisassociatedwithviralescapefromkir2dl3naturalkillercellsdatafromanobservationalcohortinsouthafrica |