The highly polymorphic killer immunoglobulin-like receptors (KIRs) and their HLA class I ligands play a central role in the regulation of natural killer (NK) cells, and in the ability of HIV-1 infected individuals to control virus replication. However, functional studies to address the significance of KIR-MHC class I interactions in immunodeficiency virus infection have been limited by the lack of defined MHC class I ligands for KIRs in non-human primate models. We recently identified Mamu-A*02, an MHC class I molecule present in approximately 20% of Indian origin rhesus macaques, as a ligand for Mamu-KIR3DL05 (3DL05). This interaction was peptide-dependent, since Mamu-A*02 tetramers folded with certain simian immunodeficiency virus (SIV) peptides, but not others, stained primary NK cells and transfected cells expressing multiple 3DL05 alleles. Consistent with the function of an inhibitory KIR, target cells expressing Mamu-A*02 (A*02) suppressed the degranulation of tetramer-positive NK cells from 3DL05+ macaques. These observations suggest that SIV, and potentially also HIV-1, may acquire changes in epitopes that increase the avidity of MHC class I ligands for inhibitory KIRs as a mechanism of immune evasion to prevent the activation of specific NK cell subsets. Using KIR- and MHC class I-defined rhesus macaques, we will specifically address this hypothesis, as well as other questions fundamental to the biology of NK cells in immunodeficiency virus infection. The first objective of this proposal (Aim 1) is to identify additional MHC class I ligands for Mamu KIR3DL01 and -KIR3DL05;two KIRs that are commonly expressed in the rhesus macaque and for which we have identified reagents for staining these receptors on primary NK cells.
This aim will build on recent work by our group to provide a broader foundation for investigating the role of KIR-MHC class I interactions in SIV infection. Our second objective (Aim 2) is to address the functional implications of viral peptides that modulate NK cell activation. We will determine the repertoire of SIV peptides that enhance or antagonize interactions with 3DL05, and will test the hypothesis that viral epitopes, which stabilize interactions with inhibitory KIRs, facilitate virus replication in the presence of NK cells bearing these receptors. Our third objective (Aim 3) is to compare longitudinal changes in 3DL05+ NK cells following SIV infection of 3DL05+/A*02+ versus 3DL05+/A*02- animals. The following questions will be addressed;Does the recognition of A*02-bound peptides stimulate or suppress the expansion of 3DL05+ NK cells? Are there phenotypic/functional differences in 3DL05+ NK cells in A*02+ versus A*02- animals? Is there a difference in the recruitment of 3DL05+ NK cells to tissues? These unprecedented studies will provide a better understanding of the importance of KIR-MHC class I interactions in immunodeficiency virus infection, and specifically the role of viral peptides in modulating NK cell activation as a mechanism of immune evasion.
We have identified an interaction between an inhibitory killer immunoglobulin-like receptor (KIR) on natural killer (NK) cells and a common MHC class I molecule in the rhesus macaque that is modulated by simian immunodeficiency virus (SIV) peptides. We will use KIR- and MHC class I-defined rhesus macaques to determine how this interaction affects the outcome of immunodeficiency virus infection, and to specifically address the role of viral peptides in modulating NK cell activation as a mechanism of immune evasion.
|Banerjee, Priyankana; Ries, Moritz; Janaka, Sanath Kumar et al. (2018) Diversification of Bw4 Specificity and Recognition of a Nonclassical MHC Class I Molecule Implicated in Maternal-Fetal Tolerance by Killer Cell Ig-like Receptors of the Rhesus Macaque. J Immunol 201:2776-2786|
|Richard, Jonathan; Prévost, Jérémie; von Bredow, Benjamin et al. (2017) BST-2 Expression Modulates Small CD4-Mimetic Sensitization of HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity. J Virol 91:|
|Arias, Juan F; Colomer-Lluch, Marta; von Bredow, Benjamin et al. (2016) Tetherin Antagonism by HIV-1 Group M Nef Proteins. J Virol :|
|Weisgrau, Kim L; Ries, Moritz; Pomplun, Nicholas et al. (2016) OMIP-035: Functional analysis of natural killer cell subsets in macaques. Cytometry A 89:799-802|
|von Bredow, Benjamin; Arias, Juan F; Heyer, Lisa N et al. (2016) Comparison of Antibody-Dependent Cell-Mediated Cytotoxicity and Virus Neutralization by HIV-1 Env-Specific Monoclonal Antibodies. J Virol 90:6127-6139|
|Hölzemer, Angelique; Thobakgale, Christina F; Jimenez Cruz, Camilo A et al. (2015) 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 Med 12:e1001900; discussion e1001900|
|Pomplun, Nicholas; Weisgrau, Kim L; Evans, David T et al. (2015) OMIP-028: activation panel for Rhesus macaque NK cell subsets. Cytometry A 87:890-3|
|Scull, Margaret A; Shi, Chao; de Jong, Ype P et al. (2015) Hepatitis C virus infects rhesus macaque hepatocytes and simianized mice. Hepatology 62:57-67|
|von Bredow, Benjamin; Arias, Juan F; Heyer, Lisa N et al. (2015) Envelope Glycoprotein Internalization Protects Human and Simian Immunodeficiency Virus-Infected Cells from Antibody-Dependent Cell-Mediated Cytotoxicity. J Virol 89:10648-55|
|Bimber, Benjamin N; Evans, David T (2015) The killer-cell immunoglobulin-like receptors of macaques. Immunol Rev 267:246-58|
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