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Differential Regulation of host cellular gene expression by HIV-1 Viral protein R (Vpr): Implications for host cell function

Janket, Michelle L (2006) Differential Regulation of host cellular gene expression by HIV-1 Viral protein R (Vpr): Implications for host cell function. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The HIV/AIDS epidemic is one of the most important public health problems facing this generation. The failure of recent vaccine trials and growing resistance to anti-retroviral drugs underscores the need for novel therapeutic strategies. Design of such therapies will depend on a detailed understanding of the mechanism of action of the HIV-1 gene products. To further that goal, we have undertaken a detailed investigation of the HIV-1 viral protein R (Vpr). We employed cDNA microarray and antibody array analyses using isogenic virus with or without Vpr to determine the effect on host cellular gene expression. Vpr induced differential regulation of 109 cellular genes representing diverse families of signaling molecules. Two gene products, NHE1 and TNF alpha, were further studied for their potential roles in Vpr-mediated apoptosis. NHE1 expression was decreased by 50% at both the protein and mRNA levels in the presence of Vpr. Vpr-mediated NHE1 downregulation correlated with a dose dependent decrease in intracellular pH as well as a decrease in the active form of the pro-survival kinase Akt. The loss of these anti-apoptotic functions of NHE1 is proposed to contribute to the apoptotic role of Vpr. The pro-inflammatory cytokine TNF alpha may also play a part in Vpr-mediated apoptosis. Macrophages infected with vpr-expressing virus secreted 1.1-8.5 fold more soluble TNF alpha in response to LPS stimulation than their counterparts infected with isogenic virus lacking Vpr expression. Fold upregulation of TNF alpha directly correlated with induction of apoptosis in uninfected lymphocytes, implicating TNF alpha regulation by Vpr in bystander cell death. Two polymorphisms in the TNF alpha promoter, positions -238 and -963, were found at a higher prevalence in donors showing the lowest and highest effect of Vpr on the TNF alpha response. These results suggest that host genetic determinants may affect bystander cell death and thus the course of HIV pathogenesis. Together, the results of this study present a molecular basis for changes induced in the host cell by HIV-1 Vpr and elucidate two potential pathways for the design of anti-retroviral therapeutics targeting HIV-1 Vpr.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Janket, Michelle Lmjanket@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairAyyavoo, Velpandivelpandi@pitt.eduVELPANDI
Committee MemberMartinson, Jeremyjmartins@pitt.eduJMARTINS
Committee MemberSmithgall, Thomastsmithga@pitt.eduTSMITHGA
Committee MemberReinhart, Todd Areinhar@pitt.eduREINHAR
Date: 16 February 2006
Date Type: Completion
Defense Date: 2 December 2005
Approval Date: 16 February 2006
Submission Date: 9 December 2005
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
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: AIDS; gene regulation; HIV; Vpr; NHE1; TNF alpha
Other ID: http://etd.library.pitt.edu/ETD/available/etd-12092005-195447/, etd-12092005-195447
Date Deposited: 10 Nov 2011 20:09
Last Modified: 15 Nov 2016 13:54
URI: http://d-scholarship.pitt.edu/id/eprint/10250

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