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Principal Investigator: Michael R Betts
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $694,301
Funding agency: National Institute of Allergy and Infectious Diseases
Increasing efforts are being made to understand whether early intervention after HIV-1 infection can enable long-
term viral control and reduction of the viral reservoir through the preservation of HIV-1-specific immune
responses. Recently, the pioneering eCLEAR phase 1b/2a clinical trial led by MPI SØgaard, found that
administration of the HIV-Env specific broadly neutralizing antibody (bNAb) 3BNC117 at antiviral therapy (ART)
initiation enhanced CD8+ T cell viral immunity and enabled viral control amongst participants harboring
3BNC117-sensitive viruses. However, the mechanisms underlying this outcome remain largely unknown.
Understanding The goal of this collaborative R01 (M Betts, UPenn, B Jones, Weill-Cornell University, and
O. SØgaard, Aarhus University) is to define the mechanisms underlying this protective outcome in order
to inform future development of targeted immunotherapy at ART initiation as an HIV cure strategy. We
hypothesize that the partial success of eCLEAR can be defined in terms of both specific mechanisms of
efficacious CD8+ T-cell responses and of the features selected in remaining reservoir-harboring cells. We will
address this hypothesis in three integrated Aims using samples directly from the eCLEAR study. In Aim 1, we
will define phenotypic, functional, and transcriptomic features of the adaptive T cell immune responses that are
modulated by bNAb treatment at ART initiation (SØgaard). In Aim 2, we will define how the HIV reservoir is
differentially modulated after prolonged ART treatment and within post-therapy viral controllers vs. non-
controllers who received 3BNC117 (Betts). In Aim 3, we will define the ability of CD8+ T cells from eCLEAR
participants who did or did not exhibit post-ART control to mediate viral control in vivo using a novel humanized
mouse model. In addition, we will modulate CD8+ T cell functions within this system to uncover specific control
mechanisms. The anticipated outcomes of our project are i) A comprehensive characterization of the
immunologic and reservoir features associated with the partial efficacy of eCLEAR, ii) Validation of underlying
mechanisms, to guide future iterations of clinical interventions at the time of ART initiation.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Affect><Anti-viral Therapy><Antibody Therapy><Antigenic Determinants><B-Cell Chronic Lymphocytic Leukemia Associated Oncogene><B-cell Leukemia 1><BCL><BCL1 Oncogene><Binding Determinants><Blood Plasma><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cell Body><Cell Function><Cell Physiology><Cell Process><Cell Surface Proteins><Cell Survival><Cell Viability><Cells><Cellular Function><Cellular Physiology><Cellular Process><Clinical><Clinical Trials><Development><Disease remission><Early Intervention><Engraftment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epitopes><Expression Signature><Frequencies><Future><Gene Expression Profile><Goals><HIV><HIV Infections><HIV-1><HIV-I><HIV1><HTLV-III Infections><HTLV-III-LAV Infections><Heterograft><Heterologous Transplantation><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Human immunodeficiency virus 1><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><Immune><Immune Interferon><Immune mediated therapy><Immune response><Immunes><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologically Directed Therapy><Immunologics><Immunotherapy><Individual><Infection><Infusion><Infusion procedures><Interferon Gamma><Interferon Type II><Interruption><Intervention><Intervention Strategies><LAV-HTLV-III><Lymphadenopathy-Associated Virus><Measures><Mediating><Modern Man><NIAID><National Institute of Allergy and Infectious Disease><Outcome><Participant><Persons><Phase><Phenotype><Plasma><Plasma Serum><Poland><Property><Remission><Reporting><Resistance><Reticuloendothelial System, Serum, Plasma><Sampling><Subcellular Process><System><T cell response><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Teff cell><Therapeutic><Time><Universities><Validation><Viral><Viral reservoir><Virus><Virus reservoir><Virus-HIV><Xenograft><Xenograft procedure><Xenotransplantation><adaptive immune response><antagonism><antagonist><antibody based therapies><antibody treatment><antibody-based therapeutics><antibody-based treatment><antiretroviral therapy><antiretroviral treatment><developmental><effector T cell><epigenetically><feature selection><gene expression pattern><gene expression signature><host response><humanized mice><humanized mouse><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunoresponse><imprint><improved><in vivo><infusions><interventional strategy><lFN-Gamma><mouse model><murine model><neutralizing antibody><novel><preservation><resistant><response><success><thymus derived lymphocyte><transcriptional profile><transcriptional signature><transcriptomics><validations><viral infectious disease treatment><xeno-transplant><xeno-transplantation>