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Principal Investigator: Edward Barker
Organization: UNIVERSITY OF WISCONSIN-MADISON
Fiscal Year: 2024
Award: $760,984
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Natural killer (NK) cells provide an immediate defense against viruses and tumors by virtue of their ability to
respond to infected or malignant cells without prior antigenic stimulation. This is accomplished through the
integration of signals from activating and inhibitory NK cell receptors (aNKRs & iNKRs). In humans and other
primate species, these include C-type lectin receptors, such as CD94/NKG2A and CD94/NKG2C, and the
highly polymorphic killer-cell immunoglobulin-like receptors (KIRs), both of which interact with MHC class I
ligands. These receptor-ligand interactions are fundamental to the ability of NK cells to differentiate healthy
cells from unhealthy cells and provide a potential mechanism of specificity for the development of “NK cell
memory”. NK cells can have a significant impact on HIV-1 infection. KIR and HLA class I polymorphisms have
been identified that are associated with lower viral loads and slower courses of disease progression and
certain NK cell subsets can kill HIV-infected cells in culture. Thus, NK cell-based therapies represent a
promising approach for targeting HIV-infected cells and reducing the size of viral reservoirs. We hypothesize
that viral peptides bound by the MHC class I ligands of aNKRs are critical to NK cell recognition and killing of
HIV/SIV-infected cells and that the adoptive transfer of ex vivo activated NK cells in combination with latency
reversal can deplete viral reservoirs in SIV-infected macaques on suppressive antiretroviral therapy (ART).
In Aim 1, we will determine the contribution of viral peptides bound by MHC class I ligands of aNKRs to NK
cell recognition of HIV- and SIV-infected cells. These studies will utilize high-throughput cellular assays to
rapidly screen viral peptides for MHC class I interactions with aNKRs and to identify substitutions that disrupt
these interactions. The corresponding changes will be introduced into HIV-1 and SIV to assess their impact on
NK cell responses to virus-infected cells. In Aim 2, we will assess the capacity of ex vivo expanded NK cells in
combination with latency reversal to deplete viral reservoirs in SIV-infected, ART-suppressed rhesus
macaques. This aim will take advantage of barcoded SIV and a potent new latency reversal agent to compare
with maximal sensitivity the ability of autologous versus allogeneic NK cell transfer to reduce the rate of viral
reactivation after discontinuing ART. In Aim 3, we will test the hypothesis that the depletion of viral reservoirs
by adaptive NK cell transfer can be enhanced by an Env-specific antibody with antibody-dependent cellular
cytotoxicity against SIV-infected cells. This aim will use a similar approach as Aim 2 to determine the extent to
which coupling NK cell effector function to the unparalleled specificity of antibodies can maximize reservoir
depletion. These unprecedented studies will provide a better understanding of the role of viral peptides in NK
cell recognition of HIV- and SIV-infected cells and an important proof-of-concept for the development of NK cell
therapies to eradicate HIV-1 reservoirs in chronically infected individuals.
Terms: <AIDS Virus><Ab-dependent cellular cytotoxicity><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Activated Natural Killer Cell><Adoptive Transfer><Agonist><Allogenic><Animals><Antibodies><Antibody Specificity><Antibody-Dependent Enhancement><Autologous><Bar Codes><Binding><Blood Plasma><C Type Lectin Receptors><CD16><CD16B><CD94><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell Therapy><Cells><Cellular Assay><Chronic><Class I Genes><Closure by Ligation><Control Animal><Coupling><Cytotoxic cell><Development><Disease><Disease Progression><Disorder><Effector Cell><Engineering><FCGR3B><FCGR3B gene><Fc Receptor III-1><Fc gamma IIIb receptor><Fc-Gamma RIII-Beta><Fc-Gamma RIIIB><FcRIIIB><Genetic Polymorphism><Genotype><HIV><HIV-1><HIV-I><HIV1><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><IgG Fc Receptor IIIB><Immune Globulins><Immunoglobulins><Individual><Infection><Intracellular Communication and Signaling><K Cells><K lymphocyte><KLRD1><KLRD1 gene><KP43><Killer Cell Lectin-Like Receptor Subfamily D, Member 1 Gene><Killer Cells><LAV-HTLV-III><Ligands><Ligation><Low Affinity IgG Fc Receptor IIIB><Low Affinity Immunoglobulin Gamma Fc Region Receptor III-B><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphadenopathy-Associated Virus><Lymphatic nodes><M mulatta><M. mulatta><MHC Class I><MHC Class I Genes><MHC binding peptide><Macaca><Macaca mulatta><Macaque><Malignant Cell><Memory><Modern Man><Molecular><Molecular Interaction><NK Cells><NK cell therapy><Natural Killer Cells><Pathway interactions><Peptide-MHC><Peptide-Major Histocompatibility Protein Complex><Peptide/MHC Complex><Peptides><Persons><Plasma><Plasma Serum><Primates><Primates Mammals><Rapid screening><Receptor Cell><Receptor Protein><Reticuloendothelial System, Serum, Plasma><Rhesus><Rhesus Macaque><Rhesus Monkey><Role><SIV><Signal Transduction><Signal Transduction Systems><Signaling><Simian Immunodeficiency Viruses><Specificity><Surface><Testing><Viral><Viral Burden><Viral Load><Viral Load result><Viral reservoir><Virus><Virus Replication><Virus reservoir><Virus-HIV><anti-cancer immunotherapy><antibody dependent cell mediated cytotoxicity><antibody dependent cytotoxicity><antibody mediated cellular cytotoxicity><antibody-dependent cell cytotoxicity><antibody-dependent cellular cytotoxicity><antibody-mediated cytotoxicity><anticancer immunotherapy><antiretroviral therapy><antiretroviral treatment><barcode><biological signal transduction><cancer cell><cancer immunotherapy><cell assay><cell mediated therapies><cell-based therapeutic><cell-based therapy><cellular therapeutic><cellular therapy><developmental><experiment><experimental research><experimental study><experiments><immune-based cancer therapies><immunotherapy for cancer><immunotherapy of cancer><lymph gland><lymph nodes><lymphnodes><natural killer cell therapy><pMHC><pathway><polymorphism><receptor><response><social role><tumor><viral multiplication><viral rebound><viral replication><virus multiplication><virus rebound>