Traditionally natural killer (NK) cells are characterized as nonspecific effector cells, providing rapid recognition and lysis of virus-infected and neoplastic cells. However, recent work has shown that NK cells can demonstrate features of adaptive memory, including long-lived epigenetic modification intracellular ?-chain deficient (Fc?R?g) memory-like NK cells that require antibodies to grant antigen-specificity. Importantly, we have recently demonstrated for the first time evidence of antigen-specific NK cell memory in any primate species by characterizing HIV/SIV-specific NK cells in RM and showing an expansion of Fc?R?g NK cells in both HIV and SIV infections. Harnessing antibody mediated effector functions for HIV-1 vaccines will require a better understanding of effector cell biology, including the function and location (i.e. mucosal, systemic) of these newly identified memory-like NK cells and the interplay with FcR and Ig polymorphisms (with Project 1, 2). This Project will explore the specific hypothesis that polymorphisms in Fc?Rs (and Ig) in RM will modulate binding to memory natural killer cells and other effector cells thus influencing vaccine responses and subsequent protection against SHIV challenge.
The specific aims for Project 3 are as follows:
AIM 1 : Determine Fc?R expression and memory NK cell profiles in humans and RM.
AIM 2 : Determine functional differences between human and RM polymorphic Fc?Rs AIM 3: Perform a RM passive immunization study with defined Fc?R genotypes/NK cell phenotype

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI120756-05
Application #
9925745
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Duke University
Department
Type
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Brown, Eric P; Weiner, Joshua A; Lin, Shu et al. (2018) Optimization and qualification of an Fc Array assay for assessments of antibodies against HIV-1/SIV. J Immunol Methods 455:24-33
Manickam, Cordelia; Nwanze, Chiadika; Ram, Daniel R et al. (2018) Progressive lentivirus infection induces natural killer cell receptor-expressing B cells in the gastrointestinal tract. AIDS 32:1571-1578
Ram, Daniel R; Manickam, Cordelia; Hueber, Brady et al. (2018) Tracking KLRC2 (NKG2C)+ memory-like NK cells in SIV+ and rhCMV+ rhesus macaques. PLoS Pathog 14:e1007104
Alter, Galit; Dowell, Karen G; Brown, Eric P et al. (2018) High-resolution definition of humoral immune response correlates of effective immunity againstĀ HIV. Mol Syst Biol 14:e7881
Wills, Saintedym; Hwang, Kwan-Ki; Liu, Pinghuang et al. (2018) HIV-1-Specific IgA Monoclonal Antibodies from an HIV-1 Vaccinee Mediate Galactosylceramide Blocking and Phagocytosis. J Virol 92:
Shah, Spandan V; Manickam, Cordelia; Ram, Daniel R et al. (2018) CMV Primes Functional Alternative Signaling in Adaptive ?g NK Cells but Is Subverted by Lentivirus Infection in Rhesus Macaques. Cell Rep 25:2766-2774.e3
Boesch, Austin W; Kappel, James H; Mahan, Alison E et al. (2018) Enrichment of high affinity subclasses and glycoforms from serum-derived IgG using Fc?Rs as affinity ligands. Biotechnol Bioeng 115:1265-1278
Cheng, Hao D; Grimm, Sebastian K; Gilman, Morgan Sa et al. (2018) Fine epitope signature of antibody neutralization breadth at the HIV-1 envelope CD4-binding site. JCI Insight 3:
Paust, Silke; Blish, Catherine A; Reeves, R Keith (2017) Redefining Memory: Building the Case for Adaptive NK Cells. J Virol 91:
Shen, Xiaoying; Bogers, Willy M; Yates, Nicole L et al. (2017) Cross-Linking of a CD4-Mimetic Miniprotein with HIV-1 Env gp140 Alters Kinetics and Specificities of Antibody Responses against HIV-1 Env in Macaques. J Virol 91:

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