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NK cell memory and help in HIV infection

Anderko, Renee R. (2022) NK cell memory and help in HIV infection. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

While natural killer (NK) cells are lauded for their killing effector function, they also play a critical role as immune helper cells, responding with great flexibility to environmental cues to provide subsequent alarm signals crucial for shaping and regulating the adaptive immune response. Most recently, the concept of immunological memory has been extended to NK cells, with the emergence of an inflated population of NK cells deficient in FcRg (FcRg−) described in the setting of HIV-1 infection. The physiological relevance of FcRg− NK cells, including their relationship with HIV-1-associated chronic inflammatory events, and their potential to be targeted to improve HIV-1 control, are poorly understood. Here, I present an in-depth analysis of the impact of chronic HIV-1 infection and long-term antiretroviral therapy (ART) on the phenotypic and functional character of NK cells, with particular attention directed toward characterizing FcRg− NK cells and exploring the reciprocal crosstalk between NK cells and dendritic cells (DCs) to enhance cellular-mediated immunity to HIV-1. Although NK cells are capable of providing immune help in response to innate stimuli during ART-mediated viral suppression, HIV-1 infection accelerates the expansion of highly differentiated FcRg− NK ‘effector memory’ cells with limited function. By specializing in antibody-specific responses, FcRg− NK cells compromise their responsiveness to DC-derived innate stimuli, leading to qualitative differences in their helper function and crosstalk with DCs. However, the potential exists for exploiting the inflated populations of FcRg− NK cells in chronic HIV-1 infection to facilitate the induction of DC-mediated cellular immunity to HIV-1 via broadly neutralizing HIV-1-specific monoclonal antibodies (bNAbs) due to their superior antibody-dependent reactivity. Improving our understanding of the specialized nature of FcRg− memory-like NK cells will be imperative for optimizing interventions to improve health outcomes and the effectiveness of HIV-1 therapies.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Anderko, Renee R.anderkor@pitt.eduanderkor0000-0003-1964-3404
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMailliard, Robbie B.rbm19@pitt.edurbm19
Committee MemberBarratt-Boyes, Simon M.smbb@pitt.edusmbb
Committee MemberRinaldo, Charles R.rinaldo@pitt.edurinaldo
Committee MemberStorkus, Walter J.storkusw@pitt.edustorkusw
Committee MemberMetes, Dianadim4@pitt.edudim4
Date: 4 January 2022
Date Type: Publication
Defense Date: 7 December 2021
Approval Date: 4 January 2022
Submission Date: 15 December 2021
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 183
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: FcRgamma negative NK cells, memory-like NK cells, NK effector memory cells, innate immunity, IL-18, natural killer cells, antiretroviral therapy
Date Deposited: 04 Jan 2022 15:30
Last Modified: 04 Jan 2022 15:30
URI: http://d-scholarship.pitt.edu/id/eprint/42078

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