Document text
Principal Investigator: Zhi Q. Yao
Organization: JAMES H QUILLEN VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
SUMMARY
The overall goal of this proposal is to elucidate the mechanisms by which chronic HIV infection promotes telomere
attrition and T cell aging, leading to hepatitis B virus (HBV) vaccine hypo-responsiveness. To this end, we will use a
model that emulates HBV vaccine response in the setting of HIV infection. Since co-infection of HBV with HIV is
common and associated with an increased morbidity and mortality, HBV vaccine is required to prevent HBV co-
infection in HIV patients. However, HBV vaccine response in HIV-infected patients is often blunted with only 30-60%
seroconversion (HBsAb > 10 IU/ml) compared to 90-95% success rate in age-matched healthy subjects (HS). This
poor vaccine response is also observed with influenza and pneumococcal vaccinations in HIV patients and other
immunocompromised hosts, including the elderly. Recently, we have found that chronic HIV or HCV infection can
cause premature T cell aging, as evidenced by overexpression of the aging markers KLRG1, DUSP6, CD57, and
p16ink4a, dysregulation of age-associated noncoding RNAs GAS5/miR21 and, in particular, accelerated telomere
attrition - suggesting excessive proliferative turnover or inadequate telomere maintenance. Telomere integrity is a
key feature of linear chromosomes that preserves genomic stability and function, whereas telomere attrition is a
hallmark of cell aging or senescence that drives cell dysfunctions and apoptosis. While telomere length is maintained
in most cases by a telomerase that prolongs telomeric DNA, telomere-associated proteins (shelterins) protect
telomeres from unwanted DNA damage response (DDR). We investigated the mechanisms of telomere attrition in
the setting of HCV and HIV infections and discovered that the cellular expression and activity of telomerase are
intact, whereas the telomeric repeat binding factor 2 (TRF2) is significantly inhibited in CD4 T cells derived from
HCV- or HIV-infected patients. Since the role of TRF2 is to protect telomeres from unwanted DNA damage and
recruit DNA repair enzymes (e.g., telomerase) access/function at telomeres, we hypothesize that: i) the mechanisms
involved in TRF2 inhibition may accelerate telomere attrition and CD4 T cell aging during HIV infection; ii) TRF2
inhibition may result in poor access/function of telomerase at telomeres during HIV infection; and iii) TRF2-mediated
telomere attrition and CD4 T cell aging may play a pivotal role in the failure of HBV vaccine in HIV-infected patients.
To test this hypothesis, we will 1) define the mechanisms involved in TRF2 inhibition and telomere attrition in T cell
aging during HIV infection; 2) determine how TRF2-mediated telomerase transport to telomeres affects T cell aging
during HIV infection; and 3) determine the impact of telomere attrition and T cell aging on HBV vaccine failure during
HIV infection and whether restoring TRF2-mediated telomere sheltering and telomerase homing machinery can
rescue CD4 T cells from telomere attrition and restore cell functions. This translational study is significant in that it
will provide a working model to explore mechanisms underlying the diminished vaccine (immune) responses in many
chronic infectious and inflammatory diseases, including but not limited to HIV. Understanding these mechanisms
may uncover novel treatment targets to improve vaccine efficacy and/or immune responses in immunocompromised
hosts. It is thus clinically significant, timely, and relevant to the Veterans as well as public health.
Terms: <AIDS Virus><APF-1><ATP-Dependent Proteolysis Factor 1><Acceleration><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Affect><Age><Aging><Anaplastic T-Lymphocyte with Horseshoe-Shaped Nucleus><Anaplastic T-Lymphocyte with Kidney-Shaped Nucleus><Apoptosis><Apoptosis Pathway><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CDK4I><CDKN2><CDKN2 Genes><CDKN2A><CDKN2A gene><CMM2><Cell Aging><Cell Body><Cell Function><Cell Physiology><Cell Process><Cell Senescence><Cells><Cellular Aging><Cellular Function><Cellular Physiology><Cellular Process><Cellular Senescence><Chromosomes><Chronic><Communicable Diseases><Cyclin-Dependent Kinase Inhibitor 2A Gene><D pneumoniae><D. pneumoniae><DNA><DNA Damage><DNA Injury><DNA Repair Enzymes><DNA Sequence><DUSP6><DUSP6 protein><Deoxyribonucleic Acid><Diplococcus pneumoniae><Disease><Disorder><Dual-Specificity Phosphatase 6><Dysfunction><Elderly><Enzyme Gene><Enzymes><Exhibits><Failure><Functional RNA><Functional disorder><Genome Stability><Genomic Stability><Goals><Grippe><HBV><HBV Vaccination><HBV Vaccine><HBV infection><HCV><HCV infection><HIV><HIV Infections><HMG-20><HTLV-III Infections><HTLV-III-LAV Infections><Hallmark Cell><Hep B vaccination><Hepatitis B Infection><Hepatitis B Vaccination><Hepatitis B Vaccines><Hepatitis B Virus><Hepatitis B immunization><Hepatitis B injection><Hepatitis B series immunization><Hepatitis B virus vaccine><Hepatitis C><Hepatitis C virus><Hepatitis C virus infection><Hepatitis, Viral, Non-A, Non-B, Parenterally-Transmitted><Hepatitus C><High Mobility Protein 20><Homing><Homologous Serum Hepatitis Virus><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><INK4><INK4A><Immune><Immune response><Immunes><Immunocompetence><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunologic Competence><Immunological Competence><Immunological response><Immunosuppressed Host><Impairment><Individual><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammatory><Influenza><LAV-HTLV-III><Lead><Length><Lymphadenopathy-Associated Virus><MAP kinase phosphatase 3><MKP3><MTS1><MTS1 Genes><Mediating><Messenger RNA><Micro RNA><MicroRNAs><Microbial Superinvasion><Modeling><Molecular><Morbidity><Morbidity - disease rate><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><PYST1><Patients><Pb element><Physiopathology><Play><Pneumococcus><Programmed Cell Death><Proteins><Public Health><Replicative Senescence><Role><S pneumoniae><S. pneumoniae><Streptococcus pneumoniae><Subcellular Process><T cell response><T-Cell Receptor Interaction><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><TCR Activation><TCR Interaction><TERF2><TERF2 gene><TP16><TSG9A><Telomerase><Telomere Maintenance><Telomere Shortening><Telomeric Repeat Binding Factor 2><Testing><Ubiquitin><Untranslated RNA><Vaccination><Vaccines><Veterans><Viral><Viral Diseases><Virus Diseases><Virus-HIV><advanced age><age associated><age correlated><age dependent><age linked><age related><age specific><ages><aging biological marker><aging biomarker><aging marker><antiretroviral therapy><antiretroviral treatment><booster dose><booster shot><booster vaccine><clinical significance><clinically significant><co-infection><coinfection><exhaustion><gas 5 RNA><gas5 RNA><geriatric><growth arrest gas-5 gene product><growth arrest specific transcript 5><heavy metal Pb><heavy metal lead><hep C><hepatitis B virus vaccination><hepatitis non A non B><host response><immune system response><immunization against hepatitis B><immunoresponse><immunosuppressed patient><improved><infected with HBV><infected with hepatitis B><infected with hepatitis B virus><infection by hepatitis c virus><infection with HBV><infection with hepatitis B virus><insight><mRNA><miRNA><miRNAs><mortality><new approaches><non A, non B hepatitis><non-A, non-B hepatitis><noncoding><novel><novel approaches><novel strategies><novel strategy><overexpress><overexpression><p14ARF><p16 Genes><p16INK4 Genes><p16INK4A Genes><p16INK4a><pathophysiology><posttranscriptional><premature><prematurity><preservation><prevent><preventing><prospective><protein function><recruit><response><senescence><senescent><senior citizen><seroconversion><social role><success><super infection><superinfection><telomere><telomere attrition><telomere loss><telomeric loss><thymus derived lymphocyte><translational study><vaccination against hepatitis B><vaccine against hepatitis B><vaccine boost><vaccine efficacy><vaccine failure><vaccine response><vaccine responsiveness><vaccine-induced response><viral infection><virus infection><virus-induced disease>