Show simple item record

dc.contributor.advisorMcKnight, C. Jamesen_US
dc.contributor.advisorWhitney, Jamesen_US
dc.contributor.authorShah, Riddhien_US
dc.date.accessioned2020-12-03T19:42:59Z
dc.date.available2020-12-03T19:42:59Z
dc.date.issued2020
dc.identifier.urihttps://hdl.handle.net/2144/41726
dc.description.abstractWhile the human immunodeficiency virus (HIV) can be managed with antiretroviral therapy (ART), there is no cure for the disorder. If ART is discontinued, viral RNA levels rapidly increase in most individuals due to the presence of a cell-mediated hidden replication competent viral burden known as the viral reservoir. In order to successfully cure this disease, a mechanism to eliminate the viral reservoir must be developed. Preliminary research completed using a toll-like-receptor agonist 7 (TLR7) has shown favorable results supporting this goal. In a simian immunodeficiency virus (SIV) model, dosing rhesus macaques (RMs) with TLR7 agonists resulted in the development of controlled viremia. A controlled RM is a SIV positive animal that is able to maintain an undetectable viral load without continued therapeutic intervention. In cases of controlled SIV/HIV, viral RNA no longer replicates despite the discontinuation of all treatment. This implies that the viral reservoir is either completely eliminated or severely reduced. In this study, we quantified expression levels of several immune checkpoint and activation markers including CD69, CD39, CXCR5, TCF7, PD-1, PD-L1, TIGIT, CTLA-4, Tim-3, and Lag-3 on isolated peripheral blood mononuclear immune cells (PBMCs) [including CD4+ T cells, CD8+ T cells, natural killer (NK) cells, and B cells] in both controlled and non-controlled RMs. Our goal was to identify possible mechanisms by which controlled RMs are able to successfully modulate the host immune response after discontinuing TLR7 agonist treatment. The subjects each received one of two different TLR7 agonists (GS-9620 and GS-986). Isolated peripheral blood mononuclear cells (PBMCs) were obtained from two controlled RMs and two non-controlled RMs. Samples were analyzed using flow cytometry to identify and quantify levels of markers above. Expression levels of PD-1 and PD-L1 were elevated in PBMCs obtained from non-controlled RMs when compared to levels seen in controlled RMs. In contrast, levels of TIGIT and CTLA4 were downregulated in samples obtained from the controlled RMs. This suggests that immune checkpoint markers responsible for viral control and SIV/HIV pathogenesis have different functional roles. Additionally, the controlled RMs showed high expression of CD69 and CD39 on B cells and increased levels of CXCR5 on CD4+ T cells. This suggests that newly activated B cells likely contribute to the observed improvements in immune function. The results obtained provide favorable support for the potential role of immune checkpoint blockade as an HIV-specific immunotherapy that may contribute to the development of a controlled population. However, it is worthwhile to note that this study was completed using a relatively small sample size (n=4). Thus, interpretations of the findings herein must be replicated with a larger sample prior to forming any definitive conclusions.en_US
dc.language.isoen_US
dc.subjectImmunologyen_US
dc.subjectHIVen_US
dc.subjectImmune checkpoint moleculesen_US
dc.subjectSIVen_US
dc.subjectTLR7en_US
dc.titleImmune checkpoint expression in SIV-infected rhesus macaques treated with TLR7 agonistsen_US
dc.typeThesis/Dissertationen_US
dc.date.updated2020-11-27T23:01:56Z
etd.degree.nameMaster of Scienceen_US
etd.degree.levelmastersen_US
etd.degree.disciplineMedical Sciencesen_US
etd.degree.grantorBoston Universityen_US


This item appears in the following Collection(s)

Show simple item record