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Disease Progression in HIV-1 and the Role of Polymorphisms in the VPR Gene

Hadi, Kevin (2012) Disease Progression in HIV-1 and the Role of Polymorphisms in the VPR Gene. Master's Thesis, University of Pittsburgh. (Unpublished)

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Disease progression in individuals infected with human immunodeficiency virus type 1 (HIV-1) normally consists of a decline of the host immunity into acquired immunodeficiency syndrome (AIDS); this is a topic of great public health significance with the rapidly increasing prevalence of HIV-1 infected individuals. However 5% of the infected population resist AIDS development and remain asymptomatic. These so called long term non progressors (LTNPs) control the virus and are able to mount an effective immunological response. The role of the HIV accessory gene, Vpr, in differential disease progression is addressed in this study. For this purpose sequences identified from LTNPs and progressors (RP) from the HIV database from Los Alamos National Laboratories were analyzed to find signature polymorphisms in the amino acid sequence of this protein. Several mutations in the coding sequence of Vpr were found to be associated with the LTNPs, in particular, the threonine at position 19 mutated to alanine (T19A) and arginine at position 90 mutated to asparagine (R90N). In contrast the following mutations were found to be associated with RPs, arginine at position 36 mutated to tryptophan (R36W), leucine at position 68 mutated to methionine (L68M), and arginine at position 85 mutated to tyrosine (R85Y). A series of in vitro assays show that mainly the RP-associated mutations exhibit changes in several canonical functions of Vpr, namely, its capacity to oligomerize, localize to the nucleus, and induce G2 cell cycle arrest. However, infecting peripheral blood mononuclear cells (PBMCs) with viruses harboring these Vpr mutations demonstrates no difference in the replication capacity of the mutants compared to wild type virus. This study provides a basis to further delineate the mechanisms of Vpr function in disease progression.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairAyyavoo, Velpandivelpandi@pitt.eduVELPANDI
Committee MemberGupta, Phalgunipgupta1@pitt.eduPGUPTA1
Committee MemberSluis-Cremer, Nicolasnps2@pitt.eduNPS2
Date: 21 September 2012
Date Type: Publication
Defense Date: 16 July 2012
Approval Date: 21 September 2012
Submission Date: 23 July 2012
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 101
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Infectious Diseases and Microbiology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: HIV-1 Disease Progression LTNP Vpr Polymorphism Mutation
Date Deposited: 21 Sep 2012 20:08
Last Modified: 21 Sep 2017 05:15


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