# Variable natural killer cell responses in the control of Epstein-Barr virus infection > **NIH NIH F32** · UNIVERSITY OF COLORADO DENVER · 2022 · $26,182 ## Abstract Project summary 1 Epstein-Barr virus (EBV) infects approximately 95% of individuals, with most having an asymptomatic, latent 2 infection. However, EBV can drive immunopathological and malignant diseases in some, resulting in >1% of 3 global cancer deaths. The immune system is critical in determining the balance between asymptomatic and 4 pathogenic infection. Natural Killer (NK) cells play an important role: NK cells recognize and kill EBV-infected 5 cells, and NK cell deficiencies lead to severe EBV disease. NK cell functions are modulated by germline-encoded 6 NK cell receptors, which engage ligands expressed on infected cells. Among these receptors are the Killer cell 7 immunoglobulin-like receptors (KIR), which recognize Human Leukocyte Antigen (HLA) as ligands. Both KIR 8 and HLA are extremely polymorphic, and their ligation is allotype-specific, such that individuals have a unique 9 repertoire of HLA and KIR allotypes that determines their NK cell response to infection. Further, the specific 10 peptide presented by HLA can alter KIR ligation, including three EBV peptides known to alter KIR-HLA binding. 11 Intriguingly, genetic variants in KIR, HLA, and EBV are individually associated with EBV disease, and I have 12 observed EBV polymorphism in positions expected to alter peptide-specific binding between KIR and HLA. 13 While these genetic associations suggest HLA, KIR, and EBV genotypes determine functionally distinct NK cell 14 responses during EBV pathogenesis, the impact of KIR/HLA genetic variation in controlling EBV infection prior 15 to disease onset, and the interactions between host and viral genetic variation, remain uncharacterized. Further, 16 the immunological mechanisms behind KIR-mediated antiviral immunity to EBV are not functionally defined. 17 The proposed research will test the hypothesis that allotype-specific ligation between KIR and HLA-peptide 18 complexes determine NK cell responses across individuals and EBV strains, resulting in genotype-dependent 19 immune control of EBV infection. Aim 1 will identify the KIR, HLA, and EBV genotypes that are individually or 20 jointly associated with circulating EBV load, using samples from 20 diverse populations. These genetic 21 associations will be integrated with KIR-HLA functional data, such as ligation avidity and signaling strength, to 22 discern the role of NK cell education and antigen recognition in controlling EBV infection. Aim 2 will complement 23 the identified genetic associations by functionally testing the ability of pairs of KIR and HLA allotypes to direct 24 NK cell cytolytic functions towards EBV-infected cells. KIR and HLA allotypes that underlie NK cell recognition 25 of EBV-infected cells will be identified, as will the EBV peptides and polymorphisms that enable or disrupt NK 26 cell killing through KIR and HLA. Together, these aims will determine the role of HLA and KIR polymorphism in 27 the NK cell-mediated control of EBV infection, providing cla... ## Key facts - **NIH application ID:** 10462904 - **Project number:** 1F32AI161790-01A1 - **Recipient organization:** UNIVERSITY OF COLORADO DENVER - **Principal Investigator:** William Hunt Palmer - **Activity code:** F32 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $26,182 - **Award type:** 1 - **Project period:** 2022-07-01 → 2022-10-08 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10462904 ## Citation > US National Institutes of Health, RePORTER application 10462904, Variable natural killer cell responses in the control of Epstein-Barr virus infection (1F32AI161790-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10462904. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*