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Elucidating the roles of αβ and γδ T cells in HIV infection

BIRADAR, SHIVKUMAR (2021) Elucidating the roles of αβ and γδ T cells in HIV infection. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Untreated HIV infection leads to acquired immunodeficiency syndrome (AIDS) in nearly all cases [1]. However, a small proportion of HIV-infected individuals, known as long-term non-progressors (LTNPs), suppress viremia to undetectable levels without antiretroviral treatment [2, 3]. Additionally, while most HIV-infected individuals display defects in T cell frequency and function, including the γδ T cell subpopulations [4, 5], these parameters are maintained in LTNPs [6-8]. Although their role in HIV infection is not well-defined, γδ T cells display anti-HIV properties in vitro [9], and their maintained numbers in LTNPs implies that they may contribute to HIV control in vivo. An alternate hypothesis for the limited disease progression noted in LTNPs is based on the infecting HIV strain itself [10, 11], as defects in HIV Nef have been shown to impact the pathogenic properties of HIV in vitro [12, 13] and are associated with nonprogressive infection [14, 15]. However, it remains unclear if these reported modifications in HIV Nef and the preservation of γδ T cell frequency demonstrated in LTNPs are mechanistically interrelated and associated with in vivo outcomes. Thus, we optimized a robust bone marrow-liver-thymus (BLTS)-huMouse (huMouse) model to elucidate the role of Nef and γδ T cells in chronic HIV infection. In doing so, we demonstrated that preventing Nef dimerization abrogates HIV viremia and associated immune dysregulation in vivo, suggesting that Nef dimerization may serve as an effective HIV therapeutic target. To our knowledge, we also demonstrate for the first time that human γδ T cell subsets can be successfully reconstituted in a huMouse model, and we show that their in vivo dynamics during infection recapitulate those observations described in humans during natural HIV infection, with a particular loss in the Vδ2 subset occurring with wild-type but not Nef-defective HIV infection. Additionally, we found that replenishing the Vδ2 T cell numbers through adoptive transfer failed to control HIV infection, but instead exacerbated viremia, with the transferred cells serving as targets for HIV infection. Importantly, this small animal model provides an effective and useful platform for in vivo mechanistic studies to explore HIV pathogenesis and HIV therapeutic strategies.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
BIRADAR, SHIVKUMARSSB38@PITT.EDUssb38
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMailliard, Robbierbm19@pitt.edurbm19
Committee MemberRinaldo, Charlesrinaldo@pitt.edurinaldo
Committee MemberBility, Mosesmtbility@pitt.edumtbility
Committee MemberLotze, Micheallotzmt@upmc.edulotzmt
Date: 10 May 2021
Date Type: Publication
Defense Date: 10 May 2021
Approval Date: 10 May 2021
Submission Date: 21 April 2021
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 128
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: gamma delta T cells, Humanized mice, HIV
Date Deposited: 10 May 2021 22:15
Last Modified: 10 May 2021 22:15
URI: http://d-scholarship.pitt.edu/id/eprint/40713

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