Frequent polymorphism at drug resistance sites in HIV-1 protease and reverse transcriptase

Mary Kearney, Sarah Palmer, Frank Maldarelli, Wei Shao, Michael A. Polis, Joann Mican, Diane Rock-Kress, Joseph Bernard Margolick, John M. Coffin, John W. Mellors

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Failure of antiretroviral therapy may result from the selection of pre-existing, drug-resistant HIV-1 variants, but the frequency and type of such variants have not been defined. OBJECTIVE: We used single genome sequencing (SGS) to characterize the frequency of polymorphism at drug resistance sites in protease (PR) and reverse transcriptase (RT) in plasma samples from antiretroviral naive individuals. METHODS: A total of 2229 pro-pol sequences in 79 plasma samples from 30 patients were analyzed by SGS. A mean of 28 single genome sequences was obtained from each sample. The frequency of mutations at all PR and RT sites was compared to those associated with drug resistance. RESULTS: We detected polymorphism at one or more drug resistance sites in 27 of 30 (90%) patients. Polymorphism at positions 179 and 215 of RT was most common, both occurring in 23% of patients. Most (68%) of other drug resistance sites were polymorphic with an average of 3.2% of genomes per sample containing at least one variant from wild type. Seven drug resistance sites were polymorphic in more than 1% of genomes: PR position 33; RT positions 69, 98, 118, 179, 210, and 215. Although frequencies of synonymous polymorphism were similar at resistance and nonresistance sites, nonsynonymous polymorphism were significantly less common at drug resistance sites, implying stronger purifying selection at these positions. CONCLUSIONS: HIV-1 variants that are polymorphic at drug resistance sites pre-exist frequently as minor species in antiretroviral naive individuals. Standard genotype techniques have grossly underestimated their frequency.

Original languageEnglish (US)
Pages (from-to)497-501
Number of pages5
JournalAIDS
Volume22
Issue number4
DOIs
StatePublished - Feb 2008

Fingerprint

Drug Resistance
RNA-Directed DNA Polymerase
Genome
Peptide Hydrolases
HIV-1
Mutation Rate
Human immunodeficiency virus 1 p16 protease
Human immunodeficiency virus 1 reverse transcriptase
Genotype
Pharmaceutical Preparations

Keywords

  • Drug resistance
  • Drug resistance polymorphisms
  • Minority drug-resistant variants
  • pro-pol diversity
  • Single genome sequencing (SGS)
  • Treatment-naive patients

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Kearney, M., Palmer, S., Maldarelli, F., Shao, W., Polis, M. A., Mican, J., ... Mellors, J. W. (2008). Frequent polymorphism at drug resistance sites in HIV-1 protease and reverse transcriptase. AIDS, 22(4), 497-501. https://doi.org/10.1097/QAD.0b013e3282f29478

Frequent polymorphism at drug resistance sites in HIV-1 protease and reverse transcriptase. / Kearney, Mary; Palmer, Sarah; Maldarelli, Frank; Shao, Wei; Polis, Michael A.; Mican, Joann; Rock-Kress, Diane; Margolick, Joseph Bernard; Coffin, John M.; Mellors, John W.

In: AIDS, Vol. 22, No. 4, 02.2008, p. 497-501.

Research output: Contribution to journalArticle

Kearney, M, Palmer, S, Maldarelli, F, Shao, W, Polis, MA, Mican, J, Rock-Kress, D, Margolick, JB, Coffin, JM & Mellors, JW 2008, 'Frequent polymorphism at drug resistance sites in HIV-1 protease and reverse transcriptase', AIDS, vol. 22, no. 4, pp. 497-501. https://doi.org/10.1097/QAD.0b013e3282f29478
Kearney M, Palmer S, Maldarelli F, Shao W, Polis MA, Mican J et al. Frequent polymorphism at drug resistance sites in HIV-1 protease and reverse transcriptase. AIDS. 2008 Feb;22(4):497-501. https://doi.org/10.1097/QAD.0b013e3282f29478
Kearney, Mary ; Palmer, Sarah ; Maldarelli, Frank ; Shao, Wei ; Polis, Michael A. ; Mican, Joann ; Rock-Kress, Diane ; Margolick, Joseph Bernard ; Coffin, John M. ; Mellors, John W. / Frequent polymorphism at drug resistance sites in HIV-1 protease and reverse transcriptase. In: AIDS. 2008 ; Vol. 22, No. 4. pp. 497-501.
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abstract = "BACKGROUND: Failure of antiretroviral therapy may result from the selection of pre-existing, drug-resistant HIV-1 variants, but the frequency and type of such variants have not been defined. OBJECTIVE: We used single genome sequencing (SGS) to characterize the frequency of polymorphism at drug resistance sites in protease (PR) and reverse transcriptase (RT) in plasma samples from antiretroviral naive individuals. METHODS: A total of 2229 pro-pol sequences in 79 plasma samples from 30 patients were analyzed by SGS. A mean of 28 single genome sequences was obtained from each sample. The frequency of mutations at all PR and RT sites was compared to those associated with drug resistance. RESULTS: We detected polymorphism at one or more drug resistance sites in 27 of 30 (90{\%}) patients. Polymorphism at positions 179 and 215 of RT was most common, both occurring in 23{\%} of patients. Most (68{\%}) of other drug resistance sites were polymorphic with an average of 3.2{\%} of genomes per sample containing at least one variant from wild type. Seven drug resistance sites were polymorphic in more than 1{\%} of genomes: PR position 33; RT positions 69, 98, 118, 179, 210, and 215. Although frequencies of synonymous polymorphism were similar at resistance and nonresistance sites, nonsynonymous polymorphism were significantly less common at drug resistance sites, implying stronger purifying selection at these positions. CONCLUSIONS: HIV-1 variants that are polymorphic at drug resistance sites pre-exist frequently as minor species in antiretroviral naive individuals. Standard genotype techniques have grossly underestimated their frequency.",
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AU - Polis, Michael A.

AU - Mican, Joann

AU - Rock-Kress, Diane

AU - Margolick, Joseph Bernard

AU - Coffin, John M.

AU - Mellors, John W.

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N2 - BACKGROUND: Failure of antiretroviral therapy may result from the selection of pre-existing, drug-resistant HIV-1 variants, but the frequency and type of such variants have not been defined. OBJECTIVE: We used single genome sequencing (SGS) to characterize the frequency of polymorphism at drug resistance sites in protease (PR) and reverse transcriptase (RT) in plasma samples from antiretroviral naive individuals. METHODS: A total of 2229 pro-pol sequences in 79 plasma samples from 30 patients were analyzed by SGS. A mean of 28 single genome sequences was obtained from each sample. The frequency of mutations at all PR and RT sites was compared to those associated with drug resistance. RESULTS: We detected polymorphism at one or more drug resistance sites in 27 of 30 (90%) patients. Polymorphism at positions 179 and 215 of RT was most common, both occurring in 23% of patients. Most (68%) of other drug resistance sites were polymorphic with an average of 3.2% of genomes per sample containing at least one variant from wild type. Seven drug resistance sites were polymorphic in more than 1% of genomes: PR position 33; RT positions 69, 98, 118, 179, 210, and 215. Although frequencies of synonymous polymorphism were similar at resistance and nonresistance sites, nonsynonymous polymorphism were significantly less common at drug resistance sites, implying stronger purifying selection at these positions. CONCLUSIONS: HIV-1 variants that are polymorphic at drug resistance sites pre-exist frequently as minor species in antiretroviral naive individuals. Standard genotype techniques have grossly underestimated their frequency.

AB - BACKGROUND: Failure of antiretroviral therapy may result from the selection of pre-existing, drug-resistant HIV-1 variants, but the frequency and type of such variants have not been defined. OBJECTIVE: We used single genome sequencing (SGS) to characterize the frequency of polymorphism at drug resistance sites in protease (PR) and reverse transcriptase (RT) in plasma samples from antiretroviral naive individuals. METHODS: A total of 2229 pro-pol sequences in 79 plasma samples from 30 patients were analyzed by SGS. A mean of 28 single genome sequences was obtained from each sample. The frequency of mutations at all PR and RT sites was compared to those associated with drug resistance. RESULTS: We detected polymorphism at one or more drug resistance sites in 27 of 30 (90%) patients. Polymorphism at positions 179 and 215 of RT was most common, both occurring in 23% of patients. Most (68%) of other drug resistance sites were polymorphic with an average of 3.2% of genomes per sample containing at least one variant from wild type. Seven drug resistance sites were polymorphic in more than 1% of genomes: PR position 33; RT positions 69, 98, 118, 179, 210, and 215. Although frequencies of synonymous polymorphism were similar at resistance and nonresistance sites, nonsynonymous polymorphism were significantly less common at drug resistance sites, implying stronger purifying selection at these positions. CONCLUSIONS: HIV-1 variants that are polymorphic at drug resistance sites pre-exist frequently as minor species in antiretroviral naive individuals. Standard genotype techniques have grossly underestimated their frequency.

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