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ANTAGONISTIC EVOLUTIONARY PATHWAYS OF HIV-1 RESISTANCE TO NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS: A VIROLOGICAL, BIOCHEMICAL AND CLINICAL INVESTIGATION

Parikh, Urvi Mahendra (2005) ANTAGONISTIC EVOLUTIONARY PATHWAYS OF HIV-1 RESISTANCE TO NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS: A VIROLOGICAL, BIOCHEMICAL AND CLINICAL INVESTIGATION. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

K65R, a lysine to arginine change at codon 65 of HIV-1 reverse transcriptase (RT), has been selected in vitro by many NRTIs (nucleoside analog RT inhibitors), but until recently, was infrequently detected in patients. Located in the fingers subdomain of RT, K65R causes NRTI resistance through a discrimination mechanism by increasing selectivity for natural deoxynucleotide triphosphate substrates (dNTP) incorporation over triphosphorylated NRTI incorporation. The thymidine analog mutations (TAMs) include the following amino acid changes in RT: M41L, D67N, K70R, L210W, T215F/Y and K219Q. Different combinations of TAMs facilitate AZT resistance by a primer unblocking mechanism, also known as an "excision" mechanism, in which the chain-terminating NRTI is removed from the nascent DNA strand to allow polymerization to resume. From in vitro and clinical observations, we proposed that K65R and TAMs represent two different pathways of NRTI resistance that exhibit bi-directional phenotypic antagonism and counterselection in vivo. We have generated several lines of evidence in support of this hypothesis: (1) HIV encoding K65R has reduced susceptibility to all NRTIs tested except those with a 3' azido in the pseudosugar component (AZT and AZA); (2) in a large clinical database, K65R is increasing in prevalence in patient isolates, whereas TAMs are decreasing in prevalence; (3) a strong negative relation exists between the frequency of K65R and specific TAMs among HIV-1 isolates in a large clinical database; (4) K65R reverses viral resistance to AZT caused by TAMs and TAMs reverse resistance to abacavir and tenofovir caused by K65R; (5) K65R antagonizes the primer unblocking activity of TAMs and TAMs antagonize discrimination by K65R; and (6) in plasma samples in which both K65R and TAMs were detected by population sequencing, K65R was not found on the same genome with T215F/Y and 2 or more other TAMs, except when the Q151M multi-drug resistance complex was also present. HIV-1 drug resistance is a significant public health problem. This work contributes to the understanding of NRTI resistance and will help to optimize current and future therapy for HIV-1 infection.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Parikh, Urvi Mahendraurvi22@yahoo.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMellors, John WMellors@dom.pitt.eduJWM1
Committee MemberParniak, Michaelparniakm@msx.dept-med.pitt.edu
Committee MemberGupta, Phalgunipgupta1@pitt.eduPGUPTA1
Committee MemberMontelaro, Ronaldrmont@pitt.eduRMONT
Date: 14 September 2005
Date Type: Completion
Defense Date: 25 July 2005
Approval Date: 14 September 2005
Submission Date: 29 July 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: combination therapy; K65R; NRTI resistance; thymidine analog mutations
Other ID: http://etd.library.pitt.edu/ETD/available/etd-07292005-120606/, etd-07292005-120606
Date Deposited: 10 Nov 2011 19:54
Last Modified: 15 Nov 2016 13:47
URI: http://d-scholarship.pitt.edu/id/eprint/8698

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