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Principal Investigator: Emily Ford
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2024
Award: $189,432
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY / ABSTRACT
Summary of Proposal: This proposal supports a 5-year mentored career development award investigating the
tissue-based immune response through the lens of a recent phase 1 immunotherapeutic vaccine trial with the
long-term goal of contributing to the development of an effective herpes simplex virus-2 (HSV-2) vaccine and
improving global health.. This trial involved three sequential doses of an immunotherapeutic vaccine, HSV529,
in individuals with symptomatic HSV-2 infection. T-cell receptor (TCR) repertoire analysis was performed of T
cells in small biopsies of the area of HSV-2 reactivation in comparison to T cells from biopsies of uninvolved skin
and HSV-2 reactive CD4+ T cells from peripheral blood to research two main lines of inquiry. The first is the
interrelatedness, over time, of the TCR repertoire of the genital skin at HSV-2 reactivation sites, the arm, and
HSV-2 specific CD4+ T cells over time; whether T cells detected in genital tissue are detectable in blood with
standard sampling techniques. The second is how these relationships and dynamics change over the course of
an immunotherapeutic vaccination. Preliminary findings suggest that some T cells increased in number after
vaccination in everyone, with very little overlap between the skin and the blood. The central hypothesis is that
T cells that respond to a vaccine targeting HSV-2 are likely to be HSV-2-specific, and that T cells seen in tissue
at high copy number over a long period of time are likely to be tissue residents. The objective of this proposal
is to learn more about these resident T cells, which are otherwise difficult to study. The rationale for this is that
vaccine development for HSV-2 has thus far not been successful, and that because there is so little overlap
between the skin and the blood, that looking directly at the tissue may help identify a viral antigen or a way to
target skin-based T cells to improve vaccine efficacy. Research plan: AIM 1a will identify the specificity of T
cells of that were seen most frequently in the region of HSV-2 reactivation, focusing on T cells that expanded in
number after immunotherapeutic vaccination, as these are the most likely to be herpes-specific, tissue-resident
cells. AIM 1b focuses on establishing the spatial location of these cells in small sections of biopsies using
fluorescent molecular tags to visualize their arrangement in skin. AIM 2 focuses on learning more about these T
cells by using transcriptional profiling, a technique that separates each of the T cells in a biopsy and looks at
them one by one to uncover the cellular processes that define the activity of each cell. We will incorporate
information from TCR repertoire analysis to interpret the results of transcriptional profiling more effectively and
accurately. This approach uses small skin samples in the most comprehensive manner available to describe the
fight between HSV-2 and the human immune system. By conducting this research with an extremely experienced
and uniquely skilled group of mentors in the rich educational environment of the FHCRC and UW, Dr. Ford will
become an effective and productive lead investigator.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Affect><Animal Model><Animal Models and Related Studies><Antigenic Determinants><Antigenic Specificity><Antigens><Area><Binding Determinants><Biopsy><Blood><Blood Cells><Blood Reticuloendothelial System><Body Tissues><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Career Development Awards><Career Development Awards and Programs><Career Development Programs K-Series><Cell Body><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chronic><Clinical><Containment><Dermatologic biopsy><Development><Disease><Disorder><Dose><Effectiveness><Epidemic><Epitope Mapping><Epitopes><Expression Signature><Future><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profile><Gene Expression Profiling><Gene Transcription><Generations><Genetic Transcription><Genital Organs><Genitalia><Goals><HHV-2><HHV2><HIV><HIV-1><HIV-I><HIV1><HSV><HSV Vaccines><HSV-2><HSV2><Health Benefit><Herpes Simplex Virus><Herpes Simplex Virus 2><Herpes Simplex Virus Type 2><Herpes Simplex Virus Vaccines><Herpes labialis Virus><Herpesvirus 2 (alpha), Human><Herpesvirus progenitalis><Histologic><Histologically><Human><Human (alpha) herpes virus 2><Human Herpesvirus 2><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human herpes simplex virus type 2><Human immunodeficiency virus 1><Immune response><Immune system><Immunocompetent><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunological response><Immunosuppressed Host><Immunotherapeutic agent><In Situ Hybridization><Individual><Infection><Investigation><Investigators><K-Awards><K-Series Research Career Programs><LAV-HTLV-III><Laboratories><Lead><Learning><Location><Lymphadenopathy-Associated Virus><MHC Receptor><Major Histocompatibility Complex Receptor><Mentors><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Natural History><Nerve Endings><Non-Polyadenylated RNA><PBMC><Pb element><Peripheral Blood Cell><Peripheral Blood Mononuclear Cell><Peripheral Nerves><Persons><Phase><Phenotype><Play><Population><Principal Investigator><Production><Productivity><Public Health><RNA><RNA Expression><RNA Gene Products><Research><Research Career Program><Research Personnel><Researchers><Ribonucleic Acid><Risk><Role><Sampling><Series><Simplexvirus><Simplexvirus Vaccines><Site><Skin><Specificity><Subcellular Process><T Cell Specificity><T cell receptor repertoire sequencing><T cell receptor sequencing><T cell response><T-Cell Antigen Receptors><T-Cell Immunologic Specificity><T-Cell Receptor><T-Cells><T-Lymphocyte><T-cell receptor repertoire><T4 Cells><T4 Lymphocytes><TCR repertoire><TCR repertoire sequencing><TCR sequencing><TCR-seq><TCRseq><Techniques><Technology><Testing><Time><Tissue Expansion><Tissues><Transcript Expression Analyses><Transcript Expression Analysis><Transcription><Transmission><Ulcer><Ulceration><Vaccination><Vaccinee><Vaccines><Viral><Viral Antigens><Virus-HIV><Visualization><Work><analyze gene expression><arm><career><classroom environment><college atmosphere><collegial atmosphere><collegiate atmosphere><cutaneous biopsy><cytokine><depository><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><education atmosphere><educational atmosphere><educational environment><experience><fighting><first responder><foot><gene expression analysis><gene expression assay><gene expression pattern><gene expression signature><global health><heavy metal Pb><heavy metal lead><herpes simplex ii><host response><human alphaherpesvirus 2><immune competent><immune drugs><immune system response><immune-based therapeutics><immunogen><immunologic therapeutics><immunoresponse><immunosuppressed patient><immunotherapeutics><immunotherapy agent><improved><in situ Hybridization Genetics><in situ Hybridization Staining Method><intellectual atmosphere><learning atmosphere><learning environment><lens><lenses><model of animal><optimism><positive attitude><programs><public health relevance><repository><resident memory T cell><school atmosphere><school climate><skills><skin biopsy><social role><thymus derived lymphocyte><tissue resident memory T cell><training atmosphere><transcriptional profile><transcriptional profiling><transcriptional signature><transcriptomics><transmission process><university atmosphere><vaccinated individual><vaccinated participant><vaccinated patient><vaccinated person><vaccinated subject><vaccination study><vaccination trial><vaccine candidate><vaccine development><vaccine efficacy><vaccine study><vaccine trial><virus antigen>