title: A viral CTL escape mutation leading to immunoglobulin-like transcript 4-mediated functional inhibition of myelomonocytic cells.
abstract: Viral mutational escape can reduce or abrogate recognition by the T cell receptor (TCR) of virus-specific CD8+ T cells. However, very little is known about the impact of cytotoxic T lymphocyte (CTL) epitope mutations on interactions between peptide-major histocompatibility complex (MHC) class I complexes and MHC class I receptors expressed on other cell types. Here, we analyzed a variant of the immunodominant human leukocyte antigen (HLA)-B2705-restricted HIV-1 Gag KK10 epitope (KRWIILGLNK) with an L to M amino acid substitution at position 6 (L6M), which arises as a CTL escape variant after primary infection but is sufficiently immunogenic to elicit a secondary, de novo HIV-1-specific CD8+ T cell response with an alternative TCR repertoire in chronic infection. In addition to altering recognition by HIV-1-specific CD8+ T cells, the HLA-B2705-KK10 L6M complex also exhibits substantially increased binding to the immunoglobulin-like transcript (ILT) receptor 4, an inhibitory MHC class I-specific receptor expressed on myelomonocytic cells. Binding of the B2705-KK10 L6M complex to ILT4 leads to a tolerogenic phenotype of myelomonocytic cells with lower surface expression of dendritic cell (DC) maturation markers and co-stimulatory molecules. These data suggest a link between CTL-driven mutational escape, altered recognition by innate MHC class I receptors on myelomonocytic cells, and functional impairment of DCs, and thus provide important new insight into biological consequences of viral sequence diversification.
authors.affiliation: Partners AIDS Research Center, Massachusetts General Hospital, and Harvard University Center for AIDS Research, Boston, MA 02129, USA.
authors.forename: Mathias
authors.initials: M
authors.lastname: Lichterfeld
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Kavanagh
authors.forename: Katie L
authors.initials: KL
authors.lastname: Williams
authors.forename: Beenu
authors.initials: B
authors.lastname: Moza
authors.forename: Stanley K
authors.initials: SK
authors.lastname: Mui
authors.forename: ToshiYuki
authors.initials: T
authors.lastname: Miura
authors.forename: Rohini
authors.initials: R
authors.lastname: Sivamurthy
authors.forename: Rachel
authors.initials: R
authors.lastname: Allgaier
authors.forename: Florencia
authors.initials: F
authors.lastname: Pereyra
authors.forename: Alicja
authors.initials: A
authors.lastname: Trocha
authors.forename: Margaret
authors.initials: M
authors.lastname: Feeney
authors.forename: Rajesh T
authors.initials: RT
authors.lastname: Gandhi
authors.forename: Eric S
authors.initials: ES
authors.lastname: Rosenberg
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: Rachel
authors.initials: R
authors.lastname: Allen
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sundberg
authors.forename: Xu G
authors.initials: XG
authors.lastname: Yu
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D006678:HIV / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D015796:HLA-B27 Antigen / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D009000:Monocytes / Q000276:immunology* / Q000821:virology; D009154:Mutation; D022423:Myeloid Cells / Q000276:immunology* / Q000821:virology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology*
chemical_list: D015796:HLA-B27 Antigen; D015395:Histocompatibility Antigens Class I; D011948:Receptors, Antigen, T-Cell