Determining the Origins of Human Immunodeficiency Virus Type 1 Drug-resistant Minority Variants in People Who Are Recently Infected Using Phylogenetic Reconstruction
Authors: Mbisa Jean L , Kirwan Peter , Tostevin Anna , Ledesma Juan , Bibby David F , Brown Alison , Myers Richard , Hassan Amin S , Murphy Gary , Asboe David , Pozniak Anton , Kirk Stuart , Gill O Noel , Sabin Caroline , Delpech Valerie , Dunn David T ,   UK HIV Drug Resistance Database, Asboe David , Pozniak Anton , Cane Patricia , Chadwick David , Churchill Duncan , Clark Duncan , Collins Simon , Delpech Valerie , Douthwaite Samuel , Dunn David , Fearnhill Esther , Porter Kholoud , Tostevin Anna , Stirrup Oliver , Fraser Christophe , Geretti Anna Maria , Gunson Rory , Hale Antony , Hué Stéphane , Lazarus Linda , Leigh-Brown Andrew , Mbisa Tamyo , Mackie Nicola , Orkin Chloe , Nastouli Eleni , Pillay Deenan , Phillips Andrew , Sabin Caroline , Smit Erasmus , Templeton Kate , Tilston Peter , Volz Erik , Williams Ian , Zhang Hongyi , Dunn David , Fairbrother Keith , Fearnhill Esther , Porter Kholoud , Tostevin Anna , Stirrup Oliver , Dawkins Justine , O’Shea Siobhan , Mullen Jane , Smit Erasmus , Mbisa Tamyo , Cox Alison , Tandy Richard , Fawcett Tracy , Hopkins Mark , Tilston Peter , Booth Clare , Garcia-Diaz Ana , Renwick Lynne , Schmid Matthias L , Payne Brendan , Chadwick David , Hubb Jonathan , Dustan Simon , Kirk Stuart , Gunson Rory , Bradley-Stewart Amanda 
Published: December 2018

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 &gt;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 &gt;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 &lt; .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 &lt; .00001).

Conclusions
Using a densely sampled HIV-infected population, we show no evidence of DRMinV transmission among recently infected individuals.