Brown, Kevin Neal
(2009)
Dendritic cell dynamics in blood and lymphoid tissues during pathogenic simian immunodeficiency virus infection.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Dendritic cells (DC) are a heterogenous population of antigen presenting cells important in both innate and adaptive immune responses. The two major subsets of DC, CD11c+ myeloid DC (mDC) and CD123+ plasmacytoid DC (pDC), are depleted in the blood of human-immunodeficiency virus (HIV) - 1 infected individuals. It has been proposed that DC loss may be due to lymph node recruitment, direct viral infection, bone marrow suppression or death, although this has not been directly addressed. Using the highly relevant, rhesus macaque/simian immunodeficiency virus (SIV) model of HIV infection, we investigated DC dynamics during acute pathogenic SIV infection and simian AIDS. We hypothesized that SIV infection causes a dysregulation of DC trafficking and death not solely dependent upon direct viral infection. The specific aims of this project are to: 1) determine the phenotypic heterogeneity of DC in blood from healthy macaques and develop a rapid assay for frequent longitudinal quantitation of absolute DC numbers; 2) determine whether mDC and pDC are recruited to lymphoid tissues in simian AIDS; 3) determine the dynamics and possible mechanisms of pDC loss and redistribution to lymphoid tissue during acute SIV infection. We found that rhesus macaque DC were more phenotypically homogeneous than their human counterparts and could be accurately quantified in small volumes of blood. In monkeys with simian AIDS, DC were depleted in both blood and secondary lymphoid tissues associated with increased spontaneous apoptosis. However, the remaining DC were phenotypically normal. During acute SIV infection, pDC responded to infection in a biphasic manner, with rapid mobilization into blood followed by depletion in both blood and lymphoid tissue. However, pDC production from bone marrow was normal and BrdU-labeling indicated increased pDC mobilization and recruitment to lymphoid tissues despite net loss of pDC. In lymph nodes, pDC were directly infected with virus, activated, and undergoing increased levels of apoptosis but retained functional TLR7 signaling. The findings in this study are significant to public health because defining the mechanisms leading to DC loss will offer new opportunities for therapeutic interventions to augment immune responses in HIV-infected individuals.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
29 January 2009 |
| Date Type: |
Completion |
| Defense Date: |
8 December 2008 |
| Approval Date: |
29 January 2009 |
| Submission Date: |
23 November 2008 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
144 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Infectious Diseases and Microbiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
TLR; trafficking; HIV; nonhuman primate |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-11232008-005530/, etd-11232008-005530 |
| Date Deposited: |
10 Nov 2011 20:05 |
| Last Modified: |
15 Nov 2016 13:52 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9770 |
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