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Evolution of DC-SIGN use revealed by fitness studies of R5 HIV-1 variants emerging during AIDS progression

BACKGROUND: At early stages of infection CCR5 is the predominant HIV-1 coreceptor, but in approximately 50% of those infected CXCR4-using viruses emerge with disease progression. This coreceptor switch is correlated with an accelerated progression. However, those that maintain virus exclusively rest...

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Autores principales: Borggren, Marie, Repits, Johanna, Kuylenstierna, Carlotta, Sterjovski, Jasminka, Churchill, Melissa J, Purcell, Damian FJ, Karlsson, Anders, Albert, Jan, Gorry, Paul R, Jansson, Marianne
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2330154/
https://www.ncbi.nlm.nih.gov/pubmed/18371209
http://dx.doi.org/10.1186/1742-4690-5-28
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author Borggren, Marie
Repits, Johanna
Kuylenstierna, Carlotta
Sterjovski, Jasminka
Churchill, Melissa J
Purcell, Damian FJ
Karlsson, Anders
Albert, Jan
Gorry, Paul R
Jansson, Marianne
author_facet Borggren, Marie
Repits, Johanna
Kuylenstierna, Carlotta
Sterjovski, Jasminka
Churchill, Melissa J
Purcell, Damian FJ
Karlsson, Anders
Albert, Jan
Gorry, Paul R
Jansson, Marianne
author_sort Borggren, Marie
collection PubMed
description BACKGROUND: At early stages of infection CCR5 is the predominant HIV-1 coreceptor, but in approximately 50% of those infected CXCR4-using viruses emerge with disease progression. This coreceptor switch is correlated with an accelerated progression. However, those that maintain virus exclusively restricted to CCR5 (R5) also develop AIDS. We have previously reported that R5 variants in these "non-switch virus" patients evolve during disease progression towards a more replicative phenotype exhibiting altered CCR5 coreceptor interactions. DC-SIGN is a C-type lectin expressed by dendritic cells that HIV-1 may bind and utilize for enhanced infection of T cells in trans. To further explore the evolution of the R5 phenotype we analyzed sequential R5 isolates obtained before and after AIDS onset, i.e. at the chronic stage and during end-stage disease, with regard to efficiency of DC-SIGN use in trans-infections. RESULTS: Results from binding and trans-infection assays showed that R5 viruses emerging during end-stage AIDS disease displayed reduced ability to use DC-SIGN. To better understand viral determinants underlying altered DC-SIGN usage by R5 viruses, we cloned and sequenced the HIV-1 env gene. We found that end-stage R5 viruses lacked potential N-linked glycosylation sites (PNGS) in the gp120 V2 and V4 regions, which were present in the majority of the chronic stage R5 variants. One of these sites, amino acid position 160 (aa160) in the V2 region, also correlated with efficient use of DC-SIGN for binding and trans-infections. In fitness assays, where head-to-head competitions between chronic stage and AIDS R5 viruses were setup in parallel direct and DC-SIGN-mediated infections, results were further supported. Competitions revealed that R5 viruses obtained before AIDS onset, containing the V2 PNGS at aa160, were selected for in the trans-infection. Whereas, in agreement with our previous studies, the opposite was seen in direct target cell infections where end-stage viruses out-competed the chronic stage viruses. CONCLUSION: Results of our study suggest R5 virus variants with diverse fitness for direct and DC-SIGN-mediated trans-infections evolve within infected individuals at end-stage disease. In addition, our results point to the importance of a glycosylation site within the gp120 V2 region for efficient DC-SIGN use of HIV-1 R5 viruses.
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spelling pubmed-23301542008-04-25 Evolution of DC-SIGN use revealed by fitness studies of R5 HIV-1 variants emerging during AIDS progression Borggren, Marie Repits, Johanna Kuylenstierna, Carlotta Sterjovski, Jasminka Churchill, Melissa J Purcell, Damian FJ Karlsson, Anders Albert, Jan Gorry, Paul R Jansson, Marianne Retrovirology Research BACKGROUND: At early stages of infection CCR5 is the predominant HIV-1 coreceptor, but in approximately 50% of those infected CXCR4-using viruses emerge with disease progression. This coreceptor switch is correlated with an accelerated progression. However, those that maintain virus exclusively restricted to CCR5 (R5) also develop AIDS. We have previously reported that R5 variants in these "non-switch virus" patients evolve during disease progression towards a more replicative phenotype exhibiting altered CCR5 coreceptor interactions. DC-SIGN is a C-type lectin expressed by dendritic cells that HIV-1 may bind and utilize for enhanced infection of T cells in trans. To further explore the evolution of the R5 phenotype we analyzed sequential R5 isolates obtained before and after AIDS onset, i.e. at the chronic stage and during end-stage disease, with regard to efficiency of DC-SIGN use in trans-infections. RESULTS: Results from binding and trans-infection assays showed that R5 viruses emerging during end-stage AIDS disease displayed reduced ability to use DC-SIGN. To better understand viral determinants underlying altered DC-SIGN usage by R5 viruses, we cloned and sequenced the HIV-1 env gene. We found that end-stage R5 viruses lacked potential N-linked glycosylation sites (PNGS) in the gp120 V2 and V4 regions, which were present in the majority of the chronic stage R5 variants. One of these sites, amino acid position 160 (aa160) in the V2 region, also correlated with efficient use of DC-SIGN for binding and trans-infections. In fitness assays, where head-to-head competitions between chronic stage and AIDS R5 viruses were setup in parallel direct and DC-SIGN-mediated infections, results were further supported. Competitions revealed that R5 viruses obtained before AIDS onset, containing the V2 PNGS at aa160, were selected for in the trans-infection. Whereas, in agreement with our previous studies, the opposite was seen in direct target cell infections where end-stage viruses out-competed the chronic stage viruses. CONCLUSION: Results of our study suggest R5 virus variants with diverse fitness for direct and DC-SIGN-mediated trans-infections evolve within infected individuals at end-stage disease. In addition, our results point to the importance of a glycosylation site within the gp120 V2 region for efficient DC-SIGN use of HIV-1 R5 viruses. BioMed Central 2008-03-27 /pmc/articles/PMC2330154/ /pubmed/18371209 http://dx.doi.org/10.1186/1742-4690-5-28 Text en Copyright © 2008 Borggren et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Borggren, Marie
Repits, Johanna
Kuylenstierna, Carlotta
Sterjovski, Jasminka
Churchill, Melissa J
Purcell, Damian FJ
Karlsson, Anders
Albert, Jan
Gorry, Paul R
Jansson, Marianne
Evolution of DC-SIGN use revealed by fitness studies of R5 HIV-1 variants emerging during AIDS progression
title Evolution of DC-SIGN use revealed by fitness studies of R5 HIV-1 variants emerging during AIDS progression
title_full Evolution of DC-SIGN use revealed by fitness studies of R5 HIV-1 variants emerging during AIDS progression
title_fullStr Evolution of DC-SIGN use revealed by fitness studies of R5 HIV-1 variants emerging during AIDS progression
title_full_unstemmed Evolution of DC-SIGN use revealed by fitness studies of R5 HIV-1 variants emerging during AIDS progression
title_short Evolution of DC-SIGN use revealed by fitness studies of R5 HIV-1 variants emerging during AIDS progression
title_sort evolution of dc-sign use revealed by fitness studies of r5 hiv-1 variants emerging during aids progression
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2330154/
https://www.ncbi.nlm.nih.gov/pubmed/18371209
http://dx.doi.org/10.1186/1742-4690-5-28
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