A viral CTL escape mutation leading to immunoglobulin-like transcript 4-mediated functional inhibition of myelomonocytic cells.
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.
Lichterfeld
Mathias
M
Partners AIDS Research Center, Massachusetts General Hospital, and Harvard University Center for AIDS Research, Boston, MA 02129, USA.
Kavanagh
Daniel G
DG
Williams
Katie L
KL
Moza
Beenu
B
Mui
Stanley K
SK
Miura
ToshiYuki
T
Sivamurthy
Rohini
R
Allgaier
Rachel
R
Pereyra
Florencia
F
Trocha
Alicja
A
Feeney
Margaret
M
Gandhi
Rajesh T
RT
Rosenberg
Eric S
ES
Altfeld
Marcus
M
Allen
Todd M
TM
Allen
Rachel
R
Walker
Bruce D
BD
Sundberg
Eric J
EJ
Yu
Xu G
XG
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*
D015796:HLA-B27 Antigen; D015395:Histocompatibility Antigens Class I; D011948:Receptors, Antigen, T-Cell