Increasing prevalence of K65K and K66K in HIV-1 subtype B reverse transcriptase

Sushama Telwatte, Chanson J. Brumme, Anna C. Hearps, Catherine Frances Mary Latham, Joshua A. Hayward, Secondo Sonza, Nicolas Sluis-Cremer, P. Richard Harrigan, Gilda Tachedjian

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Objective: Synonymous substitutions K65K/K66K in HIV-1 reverse transcriptase alleviate fitness and fidelity defects in HIV-1 molecular clones harboring thymidine analogue mutations (TAMs); however, their potential for transmission and persistence is unknown. Here, we investigated the temporal appearance of K65K/K66K relative to TAMs in a HIV-1 cohort, their prevalence over time, and their impact on viral fitness in the context of patient-derived reverse transcriptase sequences. Methods: Retrospective analyses of the temporal appearance and longitudinal prevalence of synonymous substitutions and drug resistance mutations were performed using the British Columbia Centre for Excellence in HIV/AIDS Drug Treatment Program (DTP) database. Plasma-derived HIV-1 from the DTP was used to generate infectious molecular clones. Growth competition assays were performed to determine viral fitness. Results: The prevalence of K65K/K66K in drug-naïve individuals tripled from 11% in 1997 to 37% in 2014 (P<0.0001, n=5221), with K66K mainly accounting for the increase. These mutations emerged in drug-treated individuals without TAMs in 14% of the cohort and conferred a fitness advantage in the context of patient-derived multidrugresistant (MDR) virus in the absence of drug. Conclusion: The appearance of K65K/K66K in drug-treated individuals was largely independent of TAMs, suggesting alternative factors are likely associated with their emergence. The increasing K65K/K66K prevalence to over a third of treatment-naïve individuals in the mostly subtype B DTP cohort and their ability to confer a fitness advantage to multidrug-resistant virus might explain the transmission and persistence of virus harbouring K65K/K66K in untreated individuals, and highlights their role in adaptive HIV-1 evolution.

Original languageEnglish
Pages (from-to)2787-2793
Number of pages7
JournalAIDS
Volume30
Issue number18
DOIs
Publication statusPublished - 28 Nov 2016

Keywords

  • Drug resistance
  • Fitness
  • HIV-1
  • Replicative capacity
  • Synonymous mutations
  • Thymidine analogue mutations
  • Transmitted drug resistance

Cite this

Telwatte, Sushama ; Brumme, Chanson J. ; Hearps, Anna C. ; Latham, Catherine Frances Mary ; Hayward, Joshua A. ; Sonza, Secondo ; Sluis-Cremer, Nicolas ; Harrigan, P. Richard ; Tachedjian, Gilda. / Increasing prevalence of K65K and K66K in HIV-1 subtype B reverse transcriptase. In: AIDS. 2016 ; Vol. 30, No. 18. pp. 2787-2793.
@article{38e9827d1aa84b898dd386fa36b754a1,
title = "Increasing prevalence of K65K and K66K in HIV-1 subtype B reverse transcriptase",
abstract = "Objective: Synonymous substitutions K65K/K66K in HIV-1 reverse transcriptase alleviate fitness and fidelity defects in HIV-1 molecular clones harboring thymidine analogue mutations (TAMs); however, their potential for transmission and persistence is unknown. Here, we investigated the temporal appearance of K65K/K66K relative to TAMs in a HIV-1 cohort, their prevalence over time, and their impact on viral fitness in the context of patient-derived reverse transcriptase sequences. Methods: Retrospective analyses of the temporal appearance and longitudinal prevalence of synonymous substitutions and drug resistance mutations were performed using the British Columbia Centre for Excellence in HIV/AIDS Drug Treatment Program (DTP) database. Plasma-derived HIV-1 from the DTP was used to generate infectious molecular clones. Growth competition assays were performed to determine viral fitness. Results: The prevalence of K65K/K66K in drug-na{\"i}ve individuals tripled from 11{\%} in 1997 to 37{\%} in 2014 (P<0.0001, n=5221), with K66K mainly accounting for the increase. These mutations emerged in drug-treated individuals without TAMs in 14{\%} of the cohort and conferred a fitness advantage in the context of patient-derived multidrugresistant (MDR) virus in the absence of drug. Conclusion: The appearance of K65K/K66K in drug-treated individuals was largely independent of TAMs, suggesting alternative factors are likely associated with their emergence. The increasing K65K/K66K prevalence to over a third of treatment-na{\"i}ve individuals in the mostly subtype B DTP cohort and their ability to confer a fitness advantage to multidrug-resistant virus might explain the transmission and persistence of virus harbouring K65K/K66K in untreated individuals, and highlights their role in adaptive HIV-1 evolution.",
keywords = "Drug resistance, Fitness, HIV-1, Replicative capacity, Synonymous mutations, Thymidine analogue mutations, Transmitted drug resistance",
author = "Sushama Telwatte and Brumme, {Chanson J.} and Hearps, {Anna C.} and Latham, {Catherine Frances Mary} and Hayward, {Joshua A.} and Secondo Sonza and Nicolas Sluis-Cremer and Harrigan, {P. Richard} and Gilda Tachedjian",
year = "2016",
month = "11",
day = "28",
doi = "10.1097/QAD.0000000000001272",
language = "English",
volume = "30",
pages = "2787--2793",
journal = "AIDS",
issn = "0269-9370",
publisher = "Lippincott Williams & Wilkins",
number = "18",

}

Telwatte, S, Brumme, CJ, Hearps, AC, Latham, CFM, Hayward, JA, Sonza, S, Sluis-Cremer, N, Harrigan, PR & Tachedjian, G 2016, 'Increasing prevalence of K65K and K66K in HIV-1 subtype B reverse transcriptase', AIDS, vol. 30, no. 18, pp. 2787-2793. https://doi.org/10.1097/QAD.0000000000001272

Increasing prevalence of K65K and K66K in HIV-1 subtype B reverse transcriptase. / Telwatte, Sushama; Brumme, Chanson J.; Hearps, Anna C.; Latham, Catherine Frances Mary; Hayward, Joshua A.; Sonza, Secondo; Sluis-Cremer, Nicolas; Harrigan, P. Richard; Tachedjian, Gilda.

In: AIDS, Vol. 30, No. 18, 28.11.2016, p. 2787-2793.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Increasing prevalence of K65K and K66K in HIV-1 subtype B reverse transcriptase

AU - Telwatte, Sushama

AU - Brumme, Chanson J.

AU - Hearps, Anna C.

AU - Latham, Catherine Frances Mary

AU - Hayward, Joshua A.

AU - Sonza, Secondo

AU - Sluis-Cremer, Nicolas

AU - Harrigan, P. Richard

AU - Tachedjian, Gilda

PY - 2016/11/28

Y1 - 2016/11/28

N2 - Objective: Synonymous substitutions K65K/K66K in HIV-1 reverse transcriptase alleviate fitness and fidelity defects in HIV-1 molecular clones harboring thymidine analogue mutations (TAMs); however, their potential for transmission and persistence is unknown. Here, we investigated the temporal appearance of K65K/K66K relative to TAMs in a HIV-1 cohort, their prevalence over time, and their impact on viral fitness in the context of patient-derived reverse transcriptase sequences. Methods: Retrospective analyses of the temporal appearance and longitudinal prevalence of synonymous substitutions and drug resistance mutations were performed using the British Columbia Centre for Excellence in HIV/AIDS Drug Treatment Program (DTP) database. Plasma-derived HIV-1 from the DTP was used to generate infectious molecular clones. Growth competition assays were performed to determine viral fitness. Results: The prevalence of K65K/K66K in drug-naïve individuals tripled from 11% in 1997 to 37% in 2014 (P<0.0001, n=5221), with K66K mainly accounting for the increase. These mutations emerged in drug-treated individuals without TAMs in 14% of the cohort and conferred a fitness advantage in the context of patient-derived multidrugresistant (MDR) virus in the absence of drug. Conclusion: The appearance of K65K/K66K in drug-treated individuals was largely independent of TAMs, suggesting alternative factors are likely associated with their emergence. The increasing K65K/K66K prevalence to over a third of treatment-naïve individuals in the mostly subtype B DTP cohort and their ability to confer a fitness advantage to multidrug-resistant virus might explain the transmission and persistence of virus harbouring K65K/K66K in untreated individuals, and highlights their role in adaptive HIV-1 evolution.

AB - Objective: Synonymous substitutions K65K/K66K in HIV-1 reverse transcriptase alleviate fitness and fidelity defects in HIV-1 molecular clones harboring thymidine analogue mutations (TAMs); however, their potential for transmission and persistence is unknown. Here, we investigated the temporal appearance of K65K/K66K relative to TAMs in a HIV-1 cohort, their prevalence over time, and their impact on viral fitness in the context of patient-derived reverse transcriptase sequences. Methods: Retrospective analyses of the temporal appearance and longitudinal prevalence of synonymous substitutions and drug resistance mutations were performed using the British Columbia Centre for Excellence in HIV/AIDS Drug Treatment Program (DTP) database. Plasma-derived HIV-1 from the DTP was used to generate infectious molecular clones. Growth competition assays were performed to determine viral fitness. Results: The prevalence of K65K/K66K in drug-naïve individuals tripled from 11% in 1997 to 37% in 2014 (P<0.0001, n=5221), with K66K mainly accounting for the increase. These mutations emerged in drug-treated individuals without TAMs in 14% of the cohort and conferred a fitness advantage in the context of patient-derived multidrugresistant (MDR) virus in the absence of drug. Conclusion: The appearance of K65K/K66K in drug-treated individuals was largely independent of TAMs, suggesting alternative factors are likely associated with their emergence. The increasing K65K/K66K prevalence to over a third of treatment-naïve individuals in the mostly subtype B DTP cohort and their ability to confer a fitness advantage to multidrug-resistant virus might explain the transmission and persistence of virus harbouring K65K/K66K in untreated individuals, and highlights their role in adaptive HIV-1 evolution.

KW - Drug resistance

KW - Fitness

KW - HIV-1

KW - Replicative capacity

KW - Synonymous mutations

KW - Thymidine analogue mutations

KW - Transmitted drug resistance

UR - http://www.scopus.com/inward/record.url?scp=84988735815&partnerID=8YFLogxK

U2 - 10.1097/QAD.0000000000001272

DO - 10.1097/QAD.0000000000001272

M3 - Article

VL - 30

SP - 2787

EP - 2793

JO - AIDS

JF - AIDS

SN - 0269-9370

IS - 18

ER -