Document text
Principal Investigator: Marta Epeldegui
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $392,709
Funding agency: National Institute on Aging
PROJECT SUMMARY/ABSTRACT
Overall, the world population is aging and in the era of anti-retroviral therapy (ART) people living with HIV
(PLWH) live longer. ART has converted HIV infection into a survivable chronic infection; however,
comorbidities are a mounting clinical reality, likely related to accelerated immunosenescence. It is well
documented that HIV infection leads to accelerated aging, and HIV-1 chronic infection is considered a good
model for studying immunosenescence. The impact of aging on increased susceptibility to infections and
reduced responsiveness to vaccines is a well-known clinical problem. Antibodies are one of the first and most
important responses against pathogens and the reason for this dampened immune response with aging may
be due to age-related reduced humoral immunity (B cell immunosenescence). Humoral immunity has been
understudied in humans, particularly in lymphoid tissue, due to the difficulty of sample availability. It is not clear
how accurately changes observed in blood reflect immunosenescence processes in tissues, especially the
gastrointestinal mucosa which contains most of the body’s lymphocytes (~60%) and it is a region of high
antigen exposure. Therefore, gut-associated lymphoid tissue (GALT) represents a good model to study
lymphoid tissue in humans that is highly exposed to antigen stimulation. A growing body of literature has begun
to reveal the pathophysiological processes driving immune dysfunction of T cells, including work by our team,
which has studied the human mucosal immune compartment. It is not well understood how aging depresses
humoral immunity and there are little or no studies on humoral immunity in the mucosal immune compartment.
Compared to blood, gut mucosa contains fewer naïve cells, more activated memory cell, and more antibody
secreting cells, consistent with the high level of antigen exposure. Therefore, in this study, we propose to
analyze the individual and combined impact of age and HIV-1 on immunosenescence of humoral
immunity, especially in the highly immune active gastrointestinal tract, by quantifying B-cell immune
aging in GALT and peripheral blood in PLWH, as a model of accelerated aging, and in people without
HIV (PWOH). Our hypothesis is that natural aging and HIV-1-induced-accelerated aging diminishes the
capacity of the immune system to produce efficient antibody responses in the periphery and GALT; this will be
a result of inappropriate accumulation of memory-effector T-cells fueled by chronic persistent viral infections,
causing ineffective follicular helper T-cells, inefficient recall of cytotoxic responses, and a generalized,
persistent low-level inflammatory state. The Specific Aims to test this hypothesis are: Aim 1: To determine
age-related B cell lymphocyte senescence in the GALT versus peripheral blood compartments of PWOH and
PLWH ranging in age from 18 to ≥60-65 years. We will also study the functional aspects of B cells in terms of
antibody production and B cell receptor repertoire. Aim 2: To determine if the accelerated B lymphocyte
senescence seen in GALT affects humoral responses, using SARS-CoV-2 as a neoantigen challenge model.
Terms: <19S Gamma Globulin><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><AIDS Virus><Ab response><Acceleration><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Acute><Affect><Affinity><Age><Aging><Alimentary Canal><Antibodies><Antibody Formation><Antibody Production><Antibody Response><Antibody-Secreting Cells><Antigen Presentation><Antigens><Assay><Automobile Driving><B blood cells><B cell><B cell receptor><B cells><B-Cell Antigen Receptor><B-Cells><B-Lymphocytes><B-cell><BNT 162b2><BNT162b2><Bacteria><Bacterial Translocation><Bioassay><Biologic Models><Biological Assay><Biological Models><Blood><Blood Plasma><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><CMV><COVID-19><COVID-19 S protein><COVID-19 immunity><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID19 virus><CV-19><Cancers><Cardiovascular Diseases><Cell Aging><Cell Body><Cell Maturation><Cell Mediated Immunology><Cell Senescence><Cell-Mediated Immunity><Cells><Cellular Aging><Cellular Immune Function><Cellular Immunity><Cellular Senescence><Chronic><Circulation><Class Switching><Class Switchings><Clinical><Clonal Expansion><CoV-2><CoV2><Complex><Coronavirus Infectious Disease 2019><Cytomegalovirus><Data><Digestive Tract><Ensure><Exhibits><Exposure to><Frequencies><GI Tract><GI microbiome><Gastrointestinal Tract><Gastrointestinal tract structure><Goals><Gut Mucosa><Gut associated lymphoid tissue><H influenzae><H. influenzae><HCMV><HIV><HIV Infections><HIV infection in mucosa><HIV mucosal challenge><HIV-1><HIV-1 infection in mucosa><HIV-1 mucosal challenge><HIV-I><HIV1><HTLV-III Infections><HTLV-III-LAV Infections><Haemophilus influenzae><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Human immunodeficiency virus 1><Humoral Immunities><IgM><Immune><Immune Cell Activation><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune response><Immune system><Immunes><Immunity><Immunochemical Immunologic><Immunodeficiency and Immunosuppression Disorders><Immunoglobulin Class Switching><Immunoglobulin Class Switchings><Immunoglobulin M><Immunoglobulin-Secreting Cells><Immunologic><Immunologic Diseases><Immunological><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Immunologically><Immunologics><Immunomodulation><Individual><Inducer Cells><Inducer T-Lymphocytes><Infection><Infectious 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protein><SARS-CoV-2 immunity><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Salivary Gland Viruses><Sampling><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 immunity><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Sigmoid><Sigmoid colon><Site><Spikevax><Study models><Susceptibility><Symptoms><T-Cell Depletion><T-Cells><T-Lymphocyte><T-cell depletion therapy><T-lymphocyte depletion therapy><T4 Cells><T4 Lymphocytes><Teff cell><Testing><Time><Tissues><Vaccinated><Vaccination><Vaccines><Viral Diseases><Virus><Virus Diseases><Virus-HIV><Work><Wuhan coronavirus><accelerated aging><accelerated biological age><accelerated biological aging><adaptive immunity><age acceleration><age associated><age associated difference><age associated effects><age based difference><age correlated><age dependent><age dependent difference><age dependent variation><age difference><age effect><age linked><age related><age related difference><age related effects><age related variation><age specific><age specific difference><age-related inflammation><ages><aging effect><alimentary tract><antibody biosynthesis><antibody-based immunity><antigen challenge><antiretroviral therapy><antiretroviral treatment><cardiovascular disorder><chronic infection><co-morbid><co-morbidity><comorbidity><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 immunity><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><cytomegalovirus group><cytotoxic><differ by age><difference across age><difference in age><digestive canal><digestive tract microbiome><driving><effector T cell><enteric microbiome><exhaust><frailty><gastrointestinal><gastrointestinal microbiome><gut microbiome><gut-associated microbiome><hCoV19><host response><immune activation><immune function><immune modulation><immune regulation><immune senescence><immune system response><immunity against COVID-19><immunity against SARS-CoV-2><immunity against Severe acute respiratory syndrome coronavirus 2><immunity against coronavirus disease 2019><immunity to COVID-19><immunity to SARS-CoV-2><immunity to Severe acute respiratory syndrome coronavirus 2><immunity to coronavirus disease 2019><immunogen><immunoglobulin biosynthesis><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosenescence><impact of age><improved><infectious organism><inflamm-ageing><inflamm-aging><influence of age><intestinal biome><intestinal microbiome><lymph cell><mRNA vaccine><mRNA-1273><mRNA-based vaccine><mRNA1273><malignancy><microbial><mucosal HIV infection><mucosal HIV-1 infection><nCoV2><natural aging><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neoplasm/cancer><normal aging><normative aging><nutrient absorption><older groups><older individuals><older person><pathogen><peripheral blood><persistent infection><premature><prematurity><response><senescence><senescent><social role><spike proteins on SARS-CoV-2><thymus derived lymphocyte><vaccine response><vaccine responsiveness><vaccine-induced response><variation by age><viral infection><virus infection><virus-induced disease>