dc.creator | Abana, Chike Osita | |
dc.date.accessioned | 2020-08-24T11:53:36Z | |
dc.date.available | 2019-10-20 | |
dc.date.issued | 2017-10-20 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-10182017-171500 | |
dc.identifier.uri | http://hdl.handle.net/1803/15530 | |
dc.description.abstract | Cytomegalovirus (CMV) infection or latency reactivation is usually asymptomatic except in immune-suppressed hosts where it causes end-organ complications. CMV has also been proposed to drive cardiovascular disease in CMV-seropositive (CMV+) subjects. During latent CMV infection, CMV-specific T cells typically exhibit conventional (low magnitude) responses that form after contraction of expanded acute infection response. Yet, certain CMV epitopes induce “memory inflation” of T cells in immune-competent CMV+ subjects, causing lifelong elevated responses. Although memory inflation has been reported for class I CMV epitopes recognized by CD8+ T cells in immune-competent hosts, it has not been thoroughly examined among class II CMV epitope-specific CD4+ T cells nor in HIV-seropositive (HIV+) subjects.
The goal of this dissertation is to determine whether CD4+ T cells in HIV+ HCMV+ co-infected subjects recognize individual HCMV epitopes at elevated magnitudes. HLA-DRB1*07:01 (DR7) tetramers folded with HCMV glycoprotein-B DYSNTHSTRYV (DYS) epitope were used to identify circulating CD4+ T cells in HIV+ HCMV+ DR7+ and HIV- HCMV+ DR7+ subjects with undetectable HCMV plasma viremia.
DYS-specific (DYS+) CD4+ T cells were inflated among the HIV+ HCMV+ DR7+ subjects compared to either the HIV- HCMV+ DR7+ cohort, or to CD4+ T cells from the same co-infected cohort specific for DR7+ epitopes of another HCMV protein or other pathogens, including HIV. Importantly, the inflated response persisted for years in the co-infected subjects. These cells used highly restricted T cell receptor (TCR)-β and nearly monoclonal complementarity determining region-3 containing conserved amino-acids. DYS+ TCRα and TCRβ expression confirmed fine epitope specificity. The cells secreted TNF-α and IFN-γ upon DYS stimulation. Ex vivo, they expressed high CX3CR1, granzyme-B, CD38 and HLA-DR, but low CD28. These phenotypes are important for their similarity to phenotypes of CMV-specific CX3CR1+ CD4+ T cells proposed to cause endothelial damage in cardiovascular disease, indicating a potential role for memory-inflated T cell responses.
Inflation mechanism did not involve apoptosis suppression, increased proliferation or HIV gag cross-reactivity of the inflated cells; phenotypic and preliminary single-cell RNA sequencing analyses suggest a potential role for TCR stimulation of these cells by HCMV latently-infected vascular endothelial or lymph node stroma cells. | |
dc.format.mimetype | application/pdf | |
dc.subject | Cardiovascular disease | |
dc.subject | Tetramers | |
dc.subject | Human Immunodeficiency Virus | |
dc.subject | Cytomegalovirus | |
dc.subject | Memory inflation | |
dc.subject | single-cell RNA sequencing | |
dc.title | Characterization of elevated human cytomegalovirus-specific CD4+ T cells in HIV-infected subjects | |
dc.type | dissertation | |
dc.contributor.committeeMember | Mia A. Levy, M.D., Ph.D. | |
dc.contributor.committeeMember | Matthew J. Lang, Ph.D. | |
dc.contributor.committeeMember | Simon A. Mallal, MB.BS. | |
dc.contributor.committeeMember | Spyros A. Kalams, M.D. | |
dc.contributor.committeeMember | James E. Crowe, Jr., M.D. | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Microbiology and Immunology | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2019-10-20 | |
local.embargo.lift | 2019-10-20 | |
dc.contributor.committeeChair | Wonder P. Drake, M.D. | |