Next Article in Journal
Unusual Influenza A Viruses in Bats
Next Article in Special Issue
Drug Resistance in Non-B Subtype HIV-1: Impact of HIV-1 Reverse Transcriptase Inhibitors
Previous Article in Journal
Reply to Comment Clement et al.: (Prevalence of Antibodies against Hantaviruses in Serum and Saliva of Adults Living or Working on Farms in Yorkshire, United Kingdom)
Previous Article in Special Issue
Is Resistance to Dolutegravir Possible When This Drug Is Used in First-Line Therapy?
Article Menu

Export Article

Open AccessArticle
Viruses 2014, 6(9), 3428-3437; doi:10.3390/v6093428

Low-Frequency NNRTI-Resistant HIV-1 Variants and Relationship to Mutational Load in Antiretroviral-Naïve Subjects

1
Yale University School of Medicine, New Haven, CT 06510, USA
2
Veterans Affairs Connecticut Healthcare System, 950 Campbell Ave, Bldg 1, 5th floor, West Haven, CT 06516, USA
3
Bristol Myers-Squibb, Global Clinical Research, Wallingford, CT 06492, USA
4
Life Sciences—A Roche Company, Branford, CT 06405, USA
*
Author to whom correspondence should be addressed.
Received: 27 June 2014 / Revised: 22 August 2014 / Accepted: 3 September 2014 / Published: 16 September 2014
(This article belongs to the Special Issue HIV Drug Resistance)
View Full-Text   |   Download PDF [431 KB, uploaded 12 May 2015]   |  

Abstract

Low-frequency HIV variants possessing resistance mutations against non‑nucleoside reverse transcriptase inhibitors (NNRTI), especially at HIV reverse transcriptase (RT) amino acid (aa) positions K103 and Y181, have been shown to adversely affect treatment response. Therapeutic failure correlates with both the mutant viral variant frequency and the mutational load. We determined the prevalence of NNRTI resistance mutations at several RT aa positions in viruses from 204 antiretroviral (ARV)-naïve HIV-infected individuals using deep sequencing, and examined the relationship between mutant variant frequency and mutational load for those variants. Deep sequencing to ≥0.4% levels found variants with major NNRTI-resistance mutations having a Stanford-HIVdb algorithm value ≥30 for efavirenz and/or nevirapine in 52/204 (25.5%) ARV-naïve HIV-infected persons. Eighteen different major NNRTI mutations were identified at 11 different positions, with the majority of variants being at frequency >1%. The frequency of these variants correlated strongly with the mutational load, but this correlation weakened at low frequencies. Deep sequencing detected additional major NNRTI-resistant viral variants in treatment-naïve HIV-infected individuals. Our study suggests the significance of screening for mutations at all RT aa positions (in addition to K103 and Y181) to estimate the true burden of pre-treatment NNRTI-resistance. An important finding was that variants at low frequency had a wide range of mutational loads (>100-fold) suggesting that frequency alone may underestimate the impact of specific NNRTI-resistant variants. We recommend further evaluation of all low-frequency NNRTI-drug resistant variants with special attention given to the impact of mutational loads of these variants on treatment outcomes. View Full-Text
Keywords: NNRTI; non-nucleoside reverse transcriptase inhibitors; HIV; resistance; NNRTI resistance mutations; low frequency variants; mutational load; mutant variant frequency NNRTI; non-nucleoside reverse transcriptase inhibitors; HIV; resistance; NNRTI resistance mutations; low frequency variants; mutational load; mutant variant frequency
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

Gupta, S.; Lataillade, M.; Kyriakides, T.C.; Chiarella, J.; John, E.P.S.; Webb, S.; Moreno, E.A.; Simen, B.B.; Kozal, M.J. Low-Frequency NNRTI-Resistant HIV-1 Variants and Relationship to Mutational Load in Antiretroviral-Naïve Subjects. Viruses 2014, 6, 3428-3437.

Show more citation formats Show less citations formats

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Viruses EISSN 1999-4915 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top