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Global analysis of drug resistance a...

Chen, Lamei.

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Global analysis of drug resistance and viral fitness mutations and their evolutionary dynamics in HIV-1.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Global analysis of drug resistance and viral fitness mutations and their evolutionary dynamics in HIV-1./
Author:	Chen, Lamei.
Description:	97 p.
Notes:	Source: Dissertation Abstracts International, Volume: 66-09, Section: B, page: 4608.
Contained By:	Dissertation Abstracts International66-09B.
Subject:	Biology, Genetics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3188332
ISBN:	9780542309113

Global analysis of drug resistance and viral fitness mutations and their evolutionary dynamics in HIV-1.
Chen, Lamei.

Global analysis of drug resistance and viral fitness mutations and their evolutionary dynamics in HIV-1. - 97 p.

Source: Dissertation Abstracts International, Volume: 66-09, Section: B, page: 4608.

Thesis (Ph.D.)--University of California, Los Angeles, 2005.

Drug resistance is a major problem in the treatment of Acquired Immune Deficiency Syndrome (AIDS), due to the very high replication and mutation rate of the human immunodeficiency virus (HIV). Identification of mutations associated with drug resistance and understanding their evolutionary dynamics is critical for both individualized treatment selection and new drug design.

ISBN: 9780542309113Subjects--Topical Terms:

1017730
Biology, Genetics.

Global analysis of drug resistance and viral fitness mutations and their evolutionary dynamics in HIV-1.
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100 1 $a Chen, Lamei. $3 1915688
245 1 0 $a Global analysis of drug resistance and viral fitness mutations and their evolutionary dynamics in HIV-1.
300 $a 97 p.
500 $a Source: Dissertation Abstracts International, Volume: 66-09, Section: B, page: 4608.
500 $a Chair: Christopher J. Lee.
502 $a Thesis (Ph.D.)--University of California, Los Angeles, 2005.
520 $a Drug resistance is a major problem in the treatment of Acquired Immune Deficiency Syndrome (AIDS), due to the very high replication and mutation rate of the human immunodeficiency virus (HIV). Identification of mutations associated with drug resistance and understanding their evolutionary dynamics is critical for both individualized treatment selection and new drug design.
520 $a We have performed automated mutation analysis of HIV-1 protease and reverse transcriptase (RT) from 50,000 HIV-1 positive patient plasma samples sequenced by Specialty Laboratories Inc. from 1999 to 2003. This analysis generated &sim;2.3 million mutation data and enabled calculation of statistically significant Ka/Ks values for individual amino acid mutation in protease and RT. Positive selection analysis detected most of the known drug resistance mutations. We also discovered 163 new amino acid mutations in HIV protease and RT that are strong candidates for drug resistance or fitness.
520 $a Since amino acids at different sites can interact, a mutation at one site can actually change the selection pressure at other sites. To address this problem, we have extended the Ka/Ks concept to consider interactions with other sites, by formulating a conditional K a/Ks that measures the effects of mutations at one site on the selection pressure for mutations at another site. 412 codon pairs showed strong positive conditional relationships according to the conditional K a/Ks analysis. Based on the results of this analysis, we generated a rate diagram to show the speed of all the possible evolutionary paths the virus might follow under the combined selection of existing drug treatments. This diagram revealed specific accessory mutations that greatly accelerate the evolution of multi-drug resistance, and other "kinetic trap" mutations that block it.
520 $a To assess the robustness of our approach, we have applied it to four completely independent datasets. The Ka/Ks and conditional Ka/Ks results were highly reproducible among the four independent datasets, both qualitatively and quantitatively, suggesting that they are detecting real drug-resistance and viral fitness mutations in the wild HIV-1 population. Conditional Ka/Ks analysis can distinguish primary vs. accessory mutations for many well-studied examples, and Ka/Ks analysis of treated vs. untreated patient data can distinguish drug-resistance vs. viral fitness mutations.
590 $a School code: 0031.
650 4 $a Biology, Genetics. $3 1017730
650 4 $a Chemistry, Biochemistry. $3 1017722
650 4 $a Biology, Biostatistics. $3 1018416
690 $a 0369
690 $a 0487
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710 2 0 $a University of California, Los Angeles. $3 626622
773 0 $t Dissertation Abstracts International $g 66-09B.
790 1 0 $a Lee, Christopher J., $e advisor
790 $a 0031
791 $a Ph.D.
792 $a 2005
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3188332