Inhibition of dual/mixed tropic HIV-1 isolates by CCR5-inhibitors in primary lymphocytes and macrophages.
<h4>Background</h4>Dual/mixed-tropic HIV-1 strains are predominant in a significant proportion of patients, though little information is available regarding their replication-capacity and susceptibility against CCR5-antagonists in-vitro. The aim of the study was to analyze the replicatio...
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2013
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oai:doaj.org-article:c3d208c87511406aa2d478ba0704239f2021-11-18T07:38:11ZInhibition of dual/mixed tropic HIV-1 isolates by CCR5-inhibitors in primary lymphocytes and macrophages.1932-620310.1371/journal.pone.0068076https://doaj.org/article/c3d208c87511406aa2d478ba0704239f2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23874501/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Dual/mixed-tropic HIV-1 strains are predominant in a significant proportion of patients, though little information is available regarding their replication-capacity and susceptibility against CCR5-antagonists in-vitro. The aim of the study was to analyze the replication-capacity and susceptibility to maraviroc of HIV-1 clinical isolates with different tropism characteristics in primary monocyte-derived-macrophages (MDM), peripheral-blood-mononuclear-cells (PBMC), and CD4(+) T-lymphocytes.<h4>Methods</h4>Twenty-three HIV-1 isolates were phenotipically and genotipically characterized as R5, X4 or dual (discriminated as R5(+)/X4, R5/X4, R5/X4(+)). Phenotypic-tropism was evaluated by multiple-cycles-assay on U87MG-CD4(+)-CCR5(+)-/CXCR4(+)-expressing cells. Genotypic-tropism prediction was obtained using Geno2Pheno-algorithm (false-positive-rate [FPR] = 10%). Replication-capacity and susceptibility to maraviroc were investigated in human-primary MDM, PBMC and CD4(+) T-cells. AMD3100 was used as CXCR4-inhibitor. Infectivity of R5/Dual/X4-viruses in presence/absence of maraviroc was assessed also by total HIV-DNA, quantified by real-time polymerase-chain-reaction.<h4>Results</h4>Among 23 HIV-1 clinical isolates, phenotypic-tropism-assay distinguished 4, 17 and 2 viruses with R5-tropic, dual/mixed-, and X4-tropic characteristics, respectively. Overall, viruses defined as R5(+)/X4-tropic were found with the highest prevalence (10/23, 43.5%). The majority of isolates efficiently replicated in both PBMC and CD4(+) T-cells, regardless of their tropism, while MDM mainly sustained replication of R5- or R5(+)/X4-tropic isolates; strong correlation between viral-replication and genotypic-FPR-values was observed in MDM (rho = 0.710;p-value = 1.4e-4). In all primary cells, maraviroc inhibited viral-replication of isolates not only with pure R5- but also with dual/mixed tropism (mainly R5(+)/X4 and, to a lesser extent R5/X4 and R5/X4(+)). Finally, no main differences by comparing the total HIV-DNA with the p24-production in presence/absence of maraviroc were found.<h4>Conclusions</h4>Maraviroc is effective in-vitro against viruses with dual-characteristics in both MDM and lymphocytes, despite the potential X4-mediated escape. This suggests that the concept of HIV-entry through one of the two coreceptors "separately" may require revision, and that the use of CCR5-antagonists in patients with dual/mixed-tropic viruses may be a therapeutic-option that deserves further investigations in different clinical settings.Matteo SurdoEmanuela BalestraPatrizia SaccomandiFabiola Di SantoMarco MontanoDomenico Di CarloLoredana SarmatiStefano AquaroMassimo AndreoniValentina SvicherCarlo Federico PernoFrancesca Ceccherini-SilbersteinPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 7, p e68076 (2013) |
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Medicine R Science Q |
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Medicine R Science Q Matteo Surdo Emanuela Balestra Patrizia Saccomandi Fabiola Di Santo Marco Montano Domenico Di Carlo Loredana Sarmati Stefano Aquaro Massimo Andreoni Valentina Svicher Carlo Federico Perno Francesca Ceccherini-Silberstein Inhibition of dual/mixed tropic HIV-1 isolates by CCR5-inhibitors in primary lymphocytes and macrophages. |
| description |
<h4>Background</h4>Dual/mixed-tropic HIV-1 strains are predominant in a significant proportion of patients, though little information is available regarding their replication-capacity and susceptibility against CCR5-antagonists in-vitro. The aim of the study was to analyze the replication-capacity and susceptibility to maraviroc of HIV-1 clinical isolates with different tropism characteristics in primary monocyte-derived-macrophages (MDM), peripheral-blood-mononuclear-cells (PBMC), and CD4(+) T-lymphocytes.<h4>Methods</h4>Twenty-three HIV-1 isolates were phenotipically and genotipically characterized as R5, X4 or dual (discriminated as R5(+)/X4, R5/X4, R5/X4(+)). Phenotypic-tropism was evaluated by multiple-cycles-assay on U87MG-CD4(+)-CCR5(+)-/CXCR4(+)-expressing cells. Genotypic-tropism prediction was obtained using Geno2Pheno-algorithm (false-positive-rate [FPR] = 10%). Replication-capacity and susceptibility to maraviroc were investigated in human-primary MDM, PBMC and CD4(+) T-cells. AMD3100 was used as CXCR4-inhibitor. Infectivity of R5/Dual/X4-viruses in presence/absence of maraviroc was assessed also by total HIV-DNA, quantified by real-time polymerase-chain-reaction.<h4>Results</h4>Among 23 HIV-1 clinical isolates, phenotypic-tropism-assay distinguished 4, 17 and 2 viruses with R5-tropic, dual/mixed-, and X4-tropic characteristics, respectively. Overall, viruses defined as R5(+)/X4-tropic were found with the highest prevalence (10/23, 43.5%). The majority of isolates efficiently replicated in both PBMC and CD4(+) T-cells, regardless of their tropism, while MDM mainly sustained replication of R5- or R5(+)/X4-tropic isolates; strong correlation between viral-replication and genotypic-FPR-values was observed in MDM (rho = 0.710;p-value = 1.4e-4). In all primary cells, maraviroc inhibited viral-replication of isolates not only with pure R5- but also with dual/mixed tropism (mainly R5(+)/X4 and, to a lesser extent R5/X4 and R5/X4(+)). Finally, no main differences by comparing the total HIV-DNA with the p24-production in presence/absence of maraviroc were found.<h4>Conclusions</h4>Maraviroc is effective in-vitro against viruses with dual-characteristics in both MDM and lymphocytes, despite the potential X4-mediated escape. This suggests that the concept of HIV-entry through one of the two coreceptors "separately" may require revision, and that the use of CCR5-antagonists in patients with dual/mixed-tropic viruses may be a therapeutic-option that deserves further investigations in different clinical settings. |
| format |
article |
| author |
Matteo Surdo Emanuela Balestra Patrizia Saccomandi Fabiola Di Santo Marco Montano Domenico Di Carlo Loredana Sarmati Stefano Aquaro Massimo Andreoni Valentina Svicher Carlo Federico Perno Francesca Ceccherini-Silberstein |
| author_facet |
Matteo Surdo Emanuela Balestra Patrizia Saccomandi Fabiola Di Santo Marco Montano Domenico Di Carlo Loredana Sarmati Stefano Aquaro Massimo Andreoni Valentina Svicher Carlo Federico Perno Francesca Ceccherini-Silberstein |
| author_sort |
Matteo Surdo |
| title |
Inhibition of dual/mixed tropic HIV-1 isolates by CCR5-inhibitors in primary lymphocytes and macrophages. |
| title_short |
Inhibition of dual/mixed tropic HIV-1 isolates by CCR5-inhibitors in primary lymphocytes and macrophages. |
| title_full |
Inhibition of dual/mixed tropic HIV-1 isolates by CCR5-inhibitors in primary lymphocytes and macrophages. |
| title_fullStr |
Inhibition of dual/mixed tropic HIV-1 isolates by CCR5-inhibitors in primary lymphocytes and macrophages. |
| title_full_unstemmed |
Inhibition of dual/mixed tropic HIV-1 isolates by CCR5-inhibitors in primary lymphocytes and macrophages. |
| title_sort |
inhibition of dual/mixed tropic hiv-1 isolates by ccr5-inhibitors in primary lymphocytes and macrophages. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/c3d208c87511406aa2d478ba0704239f |
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