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Role of the TIGIT Immune Checkpoint Pathway in the Eradication of HIV Infection.

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Title:Role of the TIGIT Immune Checkpoint Pathway in the Eradication of HIV Infection.
Authors:Chew, Glen M.
Contributors:Biomedical Sciences (Tropical Medicine) (department)
Date Issued:Aug 2017
Publisher:University of Hawaiʻi at Mānoa
Abstract:HIV infection contributes substantially to global morbidity and mortality,
with no immediate promise of an effective vaccine or cure. One major obstacle to
vaccine development and therapy is to understand why HIV replication persists in
a person despite the presence of viral specific immune responses. The emerging
consensus has been that these immune cells are functionally ‘exhausted’ or
anergic, and thus, although they can recognize HIV infected cells, they are
unable to effectively keep up with rapid and dynamic viral replication in an
individual. Negative checkpoint receptors (NCRs) are associated with immune
dysfunction during chronic HIV infection. The goal of this study is to characterize
an emerging NCR, TIGIT, in the context of HIV infection. The overall hypothesis
is that TIGIT will be increased during HIV infection and limit anti-HIV responses,
targeting the TIGIT pathway will reinvigorate existing anti-HIV T cell effector
functions. Thus, these studies were conducted to elucidate the role of TIGIT in
progressive HIV infection.
We have identified a combination of NCR pathways that can be targeted,
TIGIT and PD-1 that may be responsible, at least in part, for making these
immune cells dysfunctional and exhausted and thus unable to control the virus.
We show that by blocking the TIGIT and PD-1 pathway, we can reverse the
defects of these viral-specific CD8 T cells. Furthermore, we extend our findings
to the clinically relevant nonhnuman primate model of HIV/AIDS. In addition, we
identify potential predictors of immune reinvigoration from clinically obtainable
samples. Our findings will give new directions to vaccines and therapies that will
potentially reverse these dysfunctional cells and allow them to control HIV
replication, but also serve in enhanced “shock and kill” HIV curative strategies.
Description:Ph.D. Thesis. University of Hawaiʻi at Mānoa 2017.
Rights:All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.
Appears in Collections: Ph.D. - Biomedical Sciences (Tropical Medicine)

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