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SIV increases susceptibility to tuberculosis by manipulating M. tuberculosis-specific immunological responses

Diedrich, Collin (2012) SIV increases susceptibility to tuberculosis by manipulating M. tuberculosis-specific immunological responses. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The emergence of human immunodeficiency virus-1 (HIV) exacerbated the already enormous number of cases of tuberculosis (TB) worldwide because HIV dramatically increases the susceptibility of humans to TB. The cause of this increased susceptibility to TB in HIV-infected individuals is not fully understood. In this thesis, I developed an SIV/TB cynomolgus macaque model and multiple in vitro and ex vivo assays to examine how HIV induces reactivation of latent TB and how HIV reduces various M. tuberculosis-specific immunological responses. In the animal model, I provide evidence that initial T cell depletion after SIV inoculation in monkeys with latent TB perturbs the control of the infection, and directly corresponds to the reactivation of TB. There was also a quantifiable decrease in the total number of T cells within granulomatous lung tissue in co-infected reactivated animals compared to animals with active TB without SIV. A significant decrease in IFN-γ releasing T cells in lung draining lymph nodes of co-infected monkeys compared to monkeys with active disease also was observed. In in vitro and ex vivo experiments we determined that the addition of exogenous SIVmac251 to cells from monkeys infected with M. tuberculosis (without SIV) leads to a specific decrease in TNF and IFN-γ production in M. tuberculosis-specific T cells between 12 and 24hrs after incubation. This decrease in T cell cytokine production was caused by SIV-induced disruption in antigen presenting cells. Specifically, the decrease in TNF production by M. tuberculosis-specific T cells was caused, at least in part, by SIV-induced IL-5 production by monocytes, which demonstrates a novel role for IL-5. The wide range of experiments implemented in this thesis provides novel evidence for the increased susceptibility of TB in HIV-infected individuals.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFlynn, JoAnnejoanne@pitt.eduJOANNE
Committee MemberBarratt-Boyes, Simonsmbb@pitt.eduSMBB
Committee MemberNorris, Karenkan1@pitt.eduKAN1
Committee MemberHendricks, Roberthendricksrr@upmc.eduRLH13
Committee MemberLu, Binfengbinfeng@pitt.eduBINFENG
Date: 6 March 2012
Date Type: Publication
Defense Date: 16 February 2012
Approval Date: 6 March 2012
Submission Date: 29 February 2012
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 209
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Virology and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: tuberculosis, HIV, SIV, co-infection, immunology, T cell, macrophage, IL-5, animal model, NHP
Date Deposited: 06 Mar 2012 16:55
Last Modified: 19 Dec 2016 14:38


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