title: Diminished transmission of drug resistant HIV-1 variants with reduced replication capacity in a human transmission model.
abstract: BACKGROUND
  Different patterns of drug resistance are observed in treated and therapy naïve HIV-1 infected populations. Especially the NRTI-related M184I/V variants, which are among the most frequently encountered mutations in treated patients, are underrepresented in the antiretroviral naïve population. M184I/V mutations are known to have a profound effect on viral replication and tend to revert over time in the new host. However it is debated whether a diminished transmission efficacy of HIV variants with a reduced replication capacity can also contribute to the observed discrepancy in genotypic patterns. As dendritic cells (DCs) play a pivotal role in HIV-1 transmission, we used a model containing primary human Langerhans cells (LCs) and DCs to compare the transmission efficacy M184 variants (HIV-M184V/I/T) to HIV wild type (HIV-WT). As control, we used HIV harboring the NNRTI mutation K103N (HIV-K103N) which has a minor effect on replication and is found at a similar prevalence in treated and untreated individuals.
  
  
  RESULTS
  In comparison to HIV-WT, the HIV-M184 variants were less efficiently transmitted to CCR5(+) Jurkat T cells by both LCs and DCs. The transmission rate of HIV-K103N was slightly reduced to HIV-WT in LCs and even higher than HIV-WT in DCs. Replication experiments in CCR5(+) Jurkat T cells revealed no apparent differences in replication capacity between the mutant viruses and HIV-WT. However, viral replication in LCs and DCs was in concordance with the transmission results; replication by the HIV-M184 variants was lower than replication by HIV-WT, and the level of replication of HIV-K103N was intermediate for LCs and higher than HIV-WT for DCs.
  
  
  CONCLUSIONS
  Our data demonstrate that drug resistant M184-variants display a reduced replication capacity in LCs and DCs which directly impairs their transmission efficacy. As such, diminished transmission efficacy may contribute to the lower prevalence of drug resistant variants in therapy naive individuals.
authors.affiliation: Virology, Department of Medical Microbiology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, the Netherlands. marieke_pingen@hotmail.com.|Department of Virology, Erasmus Medical Center, Rotterdam, the Netherlands. marieke_pingen@hotmail.com.
authors.forename: Marieke
authors.initials: M
authors.lastname: Pingen
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands. r.sarrami@amc.uva.nl.
authors.forename: Ramin
authors.initials: R
authors.lastname: Sarrami-Forooshani
authors.affiliation: Virology, Department of Medical Microbiology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, the Netherlands. a.m.j.wensing@umcutrecht.nl.
authors.forename: Annemarie M J
authors.initials: AM
authors.lastname: Wensing
authors.affiliation: Virology, Department of Medical Microbiology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, the Netherlands. p.m.vanham@umcutrecht.nl.
authors.forename: Petra
authors.initials: P
authors.lastname: van Ham
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands. a.a.drewniak@amc.uva.nl.
authors.forename: Agata
authors.initials: A
authors.lastname: Drewniak
authors.affiliation: Department of Virology, Erasmus Medical Center, Rotterdam, the Netherlands. c.boucher@erasmusmc.nl.
authors.forename: Charles A B
authors.initials: CA
authors.lastname: Boucher
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands. t.b.geijtenbeek@amc.uva.nl.
authors.forename: Teunis B H
authors.initials: TB
authors.lastname: Geijtenbeek
authors.affiliation: Virology, Department of Medical Microbiology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, the Netherlands. m.nijhuis@umcutrecht.nl.
authors.forename: Monique
authors.initials: M
authors.lastname: Nijhuis
mesh_terms: D002478:Cells, Cultured; D003713:Dendritic Cells / Q000821:virology*; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D014774:Virulence; D014779:Virus Replication
chemical_list: D050505:Mutant Proteins; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase