title: Evolution and viral characteristics of a long-term circulating resistant HIV-1 strain in a cluster of treatment-naive patients.
abstract: BACKGROUND
  Transmitted resistant HIV may revert to wild-type in the absence of drug pressure due to reduced replication capacity (RC). We observed eight therapy-naive patients infected with HIV harbouring four mutations at nucleoside reverse transcriptase inhibitor (NRTI) resistance-related positions: M41L, T69S, L210E and T215S. If partial reverted resistance patterns like these are detected at baseline, concerns for more extensive resistance in the quasispecies often directs selection of first-line combination antiretroviral therapy (cART) towards more complex regimens.
  
  
  METHODS
  Genotypic resistance testing and phylogenetic analysis was performed using pol sequences of 400 therapy-naive patients and 1322 patients with at least one NRTI-related mutation. Reverse transcriptase (RT) genes were cloned into a reference strain and RC was investigated.
  
  
  RESULTS
  Phylogenetic analysis showed that all eight patients are part of a transmission cluster (bootstrap value 92%). The patients resided in three distinct geographical regions and were either homosexually or heterosexually infected. Prior negative serology and analysis of base ambiguity demonstrated circulation for at least 7 years. In vivo evolution showed a mixture with wild-type (T215S/T) in only one untreated patient more than 6 years after diagnosis. The reverted resistance pattern did not confer a substantial reduction in RC compared with wild-type, explaining its persistence in vivo and long-term circulation in the population. Four patients started cART; three of them received quadruple cART. All patients showed good virological and immunological response.
  
  
  CONCLUSIONS
  Long-term circulation transcending distinct regions and transmission groups suggests reversion occurred in previous hosts in the transmission chain. Identification of clusters using epidemiological data and active-partner tracing may broaden therapeutic options in cases of transmitted resistance.
authors: Department of Medical Microbiology, Virology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: L Marije
authors: LM
authors: Hofstra
authors: Monique
authors: M
authors: Nijhuis
authors: Marieke
authors: M
authors: Pingen
authors: Tania
authors: T
authors: Mudrikova
authors: Annelies
authors: A
authors: Riezebos-Brilman
authors: Alberdina M
authors: AM
authors: Simoons-Smit
authors: Petra M
authors: PM
authors: Van Ham
authors: Wouter F W
authors: WF
authors: Bierman
authors: Annemarie M J
authors: AM
authors: Wensing
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology*; D023241:Antiretroviral Therapy, Highly Active; D003001:Cloning, Molecular; D004279:DNA, Viral / Q000235:genetics; D024882:Drug Resistance, Viral; D019143:Evolution, Molecular; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections / Q000453:epidemiology / Q000635:transmission / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D010641:Phenotype; D010802:Phylogeny; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D004279:DNA, Viral; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase
keywords: clusters; drug resistance; persistence; transmission