Document text
Principal Investigator: CHRISTOPHER A BENEDICT
Organization: LA JOLLA INSTITUTE FOR IMMUNOLOGY
Fiscal Year: 2022
Award: $615,063
Funding agency: National Institute of Allergy and Infectious Diseases
Summary
Cytomegalovirus (CMV, a b-herpesvirus) establishes a persistent infection that is endemic in humans and mice.
CMV causes acute clinical disease only if immunity is naïve or compromised, exemplifying how coevolution with
its host over millennia has resulted in a largely non-pathogenic détente. However, this `percolating' infection
imposes a huge footprint on the immune system, especially the T cell memory pool, and growing evidence
suggests this may ultimately be detrimental. Mounting a rapid CD4 T cell response correlates with protection
from CMV-associated disease and reduced viral shedding. Our lab identified the first mouse CMV (MCMV)
epitope-specific CD4 T cells. Of these, one response against the viral M09 protein expands long after systemic
viral infection is controlled, and is critical for resolving the persistent-phase of CMV replication. Our new data
show these `late-rising' M09 cells are unique with regards to their phenotype, effector function and transcriptome
when compared to conventional CD4 T cells that expand early during infection. Additionally, vaccine-induced
late-rising CD4 T cells provide potent protection against CMV challenge. Our overarching hypothesis is that
distinct immune environments during the acute and persistent phases of CMV infection promote the
expansion/differentiation of these late-rising cells that ultimately resolve persistence and promote latency
establishment. We will determine why these cells show such delayed expansion, determine whether they use
unique mechanisms of cytolysis to kill infected cells and resolve persistence and initiate studies to determine
whether similar CD4 T cells exist in CMV infected people. Together this proposal represents a comprehensive
plan using unique viral tools and omics-based approaches to elucidate how newly identified late-rising CD4 T
cells function to resolve persistent CMV replication, a question that has remained largely unaddressed to date.
Terms: <(TNF)-α><21+ years old><Acute><Adult><Adult Human><Antigenic Determinants><Autoregulation><BAC clone><BACs><Bacterial Artificial Chromosomes><Binding Determinants><Body Tissues><CD28><CD28 gene><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><CMV><CMV infection><CMV vaccine><CSIF><CSIF-10><Cachectin><Cancers><Cell Body><Cell Compartmentation><Cell Compartmentations><Cell Function><Cell Process><Cell physiology><Cell surface><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular immunotherapy><Cercopithecid herpesvirus 1><Cercopithecine Herpesvirus 1><Chronic><Clinical><Co-Stimulator><Costimulator><Cyclicity><Cytokine Synthesis Inhibitory Factor><Cytolysis><Cytomegalic Inclusion Disease><Cytomegalovirus><Cytomegalovirus Infections><Cytomegalovirus Vaccines><Data><Disease><Disorder><Environment><Epidermal Thymocyte Activating Factor><Epitopes><Equilibrium><Event><Expression Signature><GZMA><GZMA gene><Gene Expression Profile><Granzyme><HCMV><Herpes Virus B><Herpes simiae><Herpesviridae><Herpesvirus 1 (alpha), Cercopithecine><Herpesvirus 1 (beta), Murid><Herpesvirus B><Herpesvirus simiae><Herpesviruses><Homeostasis><Human><IL-10><IL-2><IL10><IL10A><IL2 Protein><Image><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune system><Immunes><Immunity><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Inclusion Disease><Infection><Interleukin 10 Precursor><Interleukin 2><Interleukin 2 Precursor><Interleukin II><Interleukin-10><Interleukin-2><Interleukine 2><Interleukine 2 Precursor><Interleukine II><LYT3><Life><Lymphocyte Mitogenic Factor><Lysis><Macrophage-Derived TNF><Malignant Neoplasms><Malignant Tumor><Mediating><Memory><Messenger RNA><Mice><Mice Mammals><Mitogenic Factor><Modern Man><Monkey B Virus><Monocyte-Derived TNF><Mouse Cytomegalovirus><Murid herpesvirus 1><Murine><Murine Cytomegalovirus><Mus><Patients><Periodicity><Persons><Phase><Phenotype><Physiological Homeostasis><Population><Protein Family><Proteins><RNA Seq><RNA sequencing><RNAseq><Recombinants><Reporter><Reporting><Resolution><Rhythmicity><Role><Salivary Gland Virus Disease><Salivary Gland Viruses><Salivary Glands><Salivary Glands Head and Neck><Simian Herpesvirus><Site><Specificity><Subcellular Process><T cell growth factor><T cell response><T memory cell><T-Cell Growth Factor><T-Cell Stimulating Factor><T-Cells><T-Lymphocyte><T-cell receptor repertoire><T4 Cells><T4 Lymphocytes><T44><T8 Cells><T8 Lymphocytes><TCR repertoire><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Thymocyte Stimulating Factor><Time><Tissues><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Vaccinated><Vaccination><Vaccines><Viral><Viral Diseases><Viral Shedding><Virus><Virus Diseases><Virus Replication><Virus Shedding><adulthood><allergic/immunologic body system><allergic/immunologic organ system><antigen processing><autoinflammatory><balance><balance function><base><cell-based immunotherapy><chronic infection><combat><cytomegalovirus group><develop a vaccine><develop vaccines><development of a vaccine><gene expression pattern><gene expression signature><global gene expression><global transcription profile><herpes virus><imaging><immune cell therapy><mRNA><malignancy><memory CD4 T cell><memory CD4 T lymphocyte><memory T lymphocyte><neoplasm/cancer><persistent infection><response><senescence><senescent><social role><thymus derived lymphocyte><tool><transcriptional profile><transcriptional signature><transcriptome><transcriptome sequencing><transcriptomics><vaccine development><vaccine for immunotherapy><vaccine immunotherapy><vaccine-based immunotherapy><viral infection><viral multiplication><viral replication><virus infection><virus multiplication><virus-induced disease>