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Primary HIV-1 strains use Nef to downmodulate HLA-E surface expression

dc.rights.licenseopenen_US
dc.contributor.authorVAN STIGT THANS, T.
dc.contributor.authorAKKO, J. I.
dc.contributor.authorNIEHRS, A.
dc.contributor.authorGARCIA-BELTRAN, W. F.
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorRICHERT, Laura
dc.contributor.authorSTURZEL, C. M.
dc.contributor.authorFORD, C. T.
dc.contributor.authorLI, H.
dc.contributor.authorOCHSENBAUER, C.
dc.contributor.authorKAPPES, J. C.
dc.contributor.authorHAHN, B. H.
dc.contributor.authorKIRCHHOFF, F.
dc.contributor.authorMARTRUS, G.
dc.contributor.authorSAUTER, D.
dc.contributor.authorALTFELD, M.
dc.contributor.authorHOLZEMER, A.
dc.date.accessioned2020-07-16T13:01:11Z
dc.date.available2020-07-16T13:01:11Z
dc.date.issued2019-10-15
dc.identifier.issn1098-5514 (Electronic) 0022-538X (Linking)en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/10493
dc.description.abstractEnHuman immunodeficiency virus type 1 (HIV-1) has evolved elaborate ways to evade immune cell recognition, including downregulation of classical HLA class I (HLA-I) from the surface of infected cells. Recent evidence identified HLA-E, a non-classical HLA-I, as an important part of the antiviral immune response to HIV-1. Changes in HLA-E surface levels and peptide presentation can prompt both CD8(+) T-cell and natural killer (NK)-cell responses to viral infections. Previous studies reported unchanged or increased HLA-E levels on HIV-1-infected cells. Here, we examined HLA-E surface levels following infection of CD4(+) T cells with primary HIV-1 strains and observed that a subset downregulates HLA-E. Two primary strains of HIV-1 inducing the strongest reduction in surface HLA-E expression were chosen for further testing. Expression of single Nef or Vpu proteins in T-cell lines as well as tail-swap experiments exchanging the cytoplasmic tail of HLA-A2 with HLA-E demonstrated that Nef modulated HLA-E surface levels in a cytoplasmic tail-dependent manner. Furthermore, infection of primary CD4(+) T cells with HIV-1 mutants showed that lack of functional Nef (and Vpu to some extent) impaired HLA-E downmodulation. Taken together, this study demonstrates for the first time that HIV-1 can downregulate HLA-E surface levels on infected primary CD4(+) T cells, potentially rendering them less vulnerable to CD8(+) T-cell recognition but at increased risk of NKG2A(+) NK-cell killing.IMPORTANCE For almost two decades, it was thought that HIV-1 selectively downregulated the highly expressed HLA-I molecules HLA-A and HLA-B from the cell surface in order to evade cytotoxic T-cell recognition, while leaving HLA-C and HLA-E molecules unaltered. It was stipulated that, thereby, HIV-1 infection maintains inhibition of NK cells via inhibitory receptors that bind HLA-C and HLA-E. This concept was recently revised when a study showed that primary HIV-1 strains reduce HLA-C surface levels, whereas the cell-line adapted HIV-1 strain NL4-3 lacks this ability. Here, we demonstrate that infection with distinct primary HIV-1 strains results in a significant downregulation of surface HLA-E levels. Given the increasing evidence for HLA-E as important modulator of CD8(+) T-cell and NKG2A(+) NK-cell function, this finding has substantial implications for future immunomodulatory approaches aimed at harnessing cytotoxic cellular immunity against HIV.
dc.language.isoENen_US
dc.subject.enSISTM
dc.title.enPrimary HIV-1 strains use Nef to downmodulate HLA-E surface expression
dc.title.alternativeJ Virolen_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1128/jvi.00719-19en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed31375574en_US
bordeaux.journalJournal of virologyen_US
bordeaux.volume93en_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - U1219en_US
bordeaux.issue20en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.teamSISTM_BPH
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.exportfalse
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