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Cellular cholesterol regulation of HIV-1 trafficking during macrophage-mediated trans infection

DeLucia, Diana (2018) Cellular cholesterol regulation of HIV-1 trafficking during macrophage-mediated trans infection. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Professional antigen presenting cells (APC: myeloid dendritic cells (DC) and macrophages (MΦ); B lymphocytes) mediate highly efficient HIV-1 infection of CD4+ T cells, termed trans infection, that could contribute to HIV-1 pathogenesis. We have previously shown that lower cholesterol content in DC and B lymphocytes is associated with a lack of HIV-1 trans infection in HIV-1 infected nonprogressors (NP). Here we assessed whether HIV-1 trans infection mediated by another major APC, MΦ, is deficient in NP due to altered cholesterol metabolism. When comparing healthy HIV-1 seronegatives (SN), rapid progressors (PR), and NP, we found that monocyte-derived MΦ from NP did not mediate HIV-1 trans infection of autologous CD4+ T cells, in contrast to efficient trans infection mediated by SN and PR MΦ. MΦ trans infection efficiency was directly associated with the number of DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN)-expressing MΦ. Significantly fewer NP MΦ expressed DC-SIGN. Unesterified (free) cholesterol in MΦ cell membranes was significantly lower in NP than PR, as well as virus internalization in early endosomes. Furthermore, simvastatin (SIMV), decreased the subpopulation of DC-SIGN+ MΦ, as well as MΦ cis and trans infection. Notably, SIMV decreased cell membrane cholesterol and led to lipid raft dissociation, effectively mimicking the incompetent APC trans infection environment characteristic of NP. Our data support that DC-SIGN and membrane cholesterol are central to MΦ trans infection, and a lack of these limits HIV-1 disease progression. Lastly, we
identified differentially expressed miRNA in NP and PR plasma which may contribute to the altered cholesterol phenotype we have identified in NP APC. Understanding the mechanisms of HIV-1 trans infection has great public health importance. For example, targeting the ability of MΦ to drive HIV-1 dissemination in trans could significantly enhance HIV-1 therapeutic strategies.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
DeLucia, Dianadmc111@pitt.edudmc111
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRappocciolo, Giovannagiovanna@pitt.edugiovanna
Committee MemberRinaldo, Charlesrinaldo@pitt.edurinaldo
Committee MemberGupta, Phalgunipgupta1@pitt.edupgupta1
Committee MemberMartinson, Jeremyjmartins@pitt.edujmartins
Committee MemberLefterov, Iliyailiya.lefterov@pitt.eduiliya.lefterov
Date: 28 June 2018
Date Type: Publication
Defense Date: 1 March 2018
Approval Date: 28 June 2018
Submission Date: 29 March 2018
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 164
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: DC-SIGN HIV-1 Disease Progression
Date Deposited: 28 Jun 2018 20:32
Last Modified: 28 Jun 2018 20:32
URI: http://d-scholarship.pitt.edu/id/eprint/33983

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