Determining the Origins of Human Immunodeficiency Virus Type 1 Drug-resistant Minority Variants in People Who Are Recently Infected Using Phylogenetic Reconstruction

Jean Mbisa*, Peter Kirwan, Anna Tostevin, Juan Ledesma, David F. Bibby, Alison Brown, Richard Myers, Amin S. Hassan, Gary Murphy, David Asboe, Anton Pozniak, Stuart Kirk, O. Noel Gill, Caroline Sabin, Valerie Delpech, David T. Dunn

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Background: Drug-resistant minority variants (DRMinVs) detected in patients who recently acquired human immunodeficiency virus type 1 (HIV-1) can be transmitted, generated de novo through virus replication, or technical errors. The first form is likely to persist and result in treatment failure, while the latter two could be stochastic and transient. Methods: Ultradeep sequencing of plasma samples from 835 individuals with recent HIV-1 infection in the United Kingdom was performed to detect DRMinVs at a mutation frequency between 2% and 20%. Sequence alignments including >110 000 HIV-1 partial pol consensus sequences from the UK HIV Drug Resistance Database (UK-HDRD), linked to epidemiological and clinical data from the HIV and AIDS Reporting System, were used for transmission cluster analysis. Transmission clusters were identified using Cluster Picker with a clade support of >90% and maximum genetic distances of 4.5% or 1.5%, the latter to limit detection to likely direct transmission events. Results: Drug-resistant majority variants (DRMajVs) were detected in 66 (7.9%) and DRMinVs in 84 (10.1%) of the recently infected individuals. High levels of clustering to sequences in UK-HDRD were observed for both DRMajV (n = 48; 72.7%) and DRMinV (n = 63; 75.0%) sequences. Of these, 43 (65.2%) with DRMajVs were in a transmission cluster with sequences that harbored the same DR mutation compared to only 3 (3.6%) sequences with DRMinVs (P <. 00001, Fisher exact test). Evidence of likely direct transmission of DRMajVs was observed for 25/66 (37.9%), whereas none were observed for the DRMinVs (P <. 00001). Conclusions: Using a densely sampled HIV-infected population, we show no evidence of DRMinV transmission among recently infected individuals.

Original languageEnglish
Pages (from-to)1136-1143
Number of pages8
JournalClinical Infectious Diseases
Volume69
Issue number7
DOIs
Publication statusPublished - 13 Sep 2019

Bibliographical note

Funding Information:
The authors thank the state of Antiviral Unit and Clinical Service Unit in the Virus Reference Department, PHE for providing laboratory support and Kieren Lythgow for additional bioinformatics support. Tey also thank the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) Blood Borne and Sexually Transmitted Infections Steering Committee: Caroline Sabin (director), Anthony Nardone (PHE lead), Catherine Mercer, Gwenda Hughes, Jackie Cassell, Greta Rait, Samreen Ijaz, Tim Rhodes, Sema Mandal, Kholoud Porter, and William Rosenberg for reviewing the manuscript.

Keywords

  • Drug-resistant minority variants
  • HIV-1
  • Recent infection
  • Replication fitness
  • Transmission cluster

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