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Diminished transmission of drug resistant HIV-1 variants with reduced replication capacity in a human transmission model

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 popula...

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Autores principales: Pingen, Marieke, Sarrami-Forooshani, Ramin, Wensing, Annemarie MJ, van Ham, Petra, Drewniak, Agata, Boucher, Charles AB, Geijtenbeek, Teunis BH, Nijhuis, Monique
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4272521/
https://www.ncbi.nlm.nih.gov/pubmed/25499671
http://dx.doi.org/10.1186/s12977-014-0113-9
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author Pingen, Marieke
Sarrami-Forooshani, Ramin
Wensing, Annemarie MJ
van Ham, Petra
Drewniak, Agata
Boucher, Charles AB
Geijtenbeek, Teunis BH
Nijhuis, Monique
author_facet Pingen, Marieke
Sarrami-Forooshani, Ramin
Wensing, Annemarie MJ
van Ham, Petra
Drewniak, Agata
Boucher, Charles AB
Geijtenbeek, Teunis BH
Nijhuis, Monique
author_sort Pingen, Marieke
collection PubMed
description 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.
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spelling pubmed-42725212014-12-21 Diminished transmission of drug resistant HIV-1 variants with reduced replication capacity in a human transmission model Pingen, Marieke Sarrami-Forooshani, Ramin Wensing, Annemarie MJ van Ham, Petra Drewniak, Agata Boucher, Charles AB Geijtenbeek, Teunis BH Nijhuis, Monique Retrovirology Research 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. BioMed Central 2014-12-14 /pmc/articles/PMC4272521/ /pubmed/25499671 http://dx.doi.org/10.1186/s12977-014-0113-9 Text en © Pingen et al.; licensee BioMed Central Ltd. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Pingen, Marieke
Sarrami-Forooshani, Ramin
Wensing, Annemarie MJ
van Ham, Petra
Drewniak, Agata
Boucher, Charles AB
Geijtenbeek, Teunis BH
Nijhuis, Monique
Diminished transmission of drug resistant HIV-1 variants with reduced replication capacity in a human transmission model
title Diminished transmission of drug resistant HIV-1 variants with reduced replication capacity in a human transmission model
title_full Diminished transmission of drug resistant HIV-1 variants with reduced replication capacity in a human transmission model
title_fullStr Diminished transmission of drug resistant HIV-1 variants with reduced replication capacity in a human transmission model
title_full_unstemmed Diminished transmission of drug resistant HIV-1 variants with reduced replication capacity in a human transmission model
title_short Diminished transmission of drug resistant HIV-1 variants with reduced replication capacity in a human transmission model
title_sort diminished transmission of drug resistant hiv-1 variants with reduced replication capacity in a human transmission model
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4272521/
https://www.ncbi.nlm.nih.gov/pubmed/25499671
http://dx.doi.org/10.1186/s12977-014-0113-9
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