Michelle Cazabat

Centre Hospitalier Universitaire de Toulouse

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Jacques Izopet

Inserm

Pierre Delobel

Centre Hospitalier Universitaire de Toulouse

B. Marchou

Inserm

Stéphanie Raymond

Centre Hospitalier Universitaire de Toulouse

Patrice Massip

Hôpital Purpan

Karine Sauné

Inserm

Christophe Pasquier

Centre Hospitalier Universitaire de Toulouse

Maud Mavigner

Emory University

Mary Réquena

Institut de Virologie

Florence Nicot

Hôpital Purpan

Cooperative Institutions

Inserm

Centre National de la Recherche Scientifique

Centre Hospitalier Universitaire de Toulouse

Université Toulouse III - Paul Sabatier

Hôpital Purpan

Université de Toulouse

Institut de Virologie

Université Paris Cité

Centre de Physiopathologie de Toulouse-Purpan

Institut Cochin

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Naïve T-Cell Depletion Related to Infection by X4 Human Immunodeficiency Virus Type 1 in Poor Immunological Responders to Highly Active Antiretroviral Therapy

Journal of Virology (2006)

Pierre Delobel Marie-Thérèse Nugeyre Michelle Cazabat Karine Sauné Christophe Pasquier

The reasons for poor CD4+ T-cell recovery in some human immunodeficiency virus (HIV)-infected subjects despite effective highly active antiretroviral therapy (HAART) remain unclear. We recently reported that CXCR4-using (X4) HIV-1 could be gradually selected in cellular reservoirs during sustained HAART. Because of the differential expression of HIV-1 coreceptors CCR5 and CXCR4 on distinct T-cell subsets, the residual replication of R5 and X4 viruses could have different impacts on T-cell homeostasis during immune reconstitution on HAART. We examined this hypothesis and the mechanisms of CD4+ T-cell restoration by comparing the virological and immunological features of 15 poor and 15 good immunological responders to HAART. We found a high frequency of X4 viruses in the poor immunological responders. But the levels of intrathymic proliferation of the two groups were similar regardless of whether they were infected by R5 or X4 virus. The frequency of recent thymic emigrants in the poor immunological responders was also similar to that found in the good immunological responders, despite their reduced numbers of naïve CD4+ T cells. Our data, rather, suggest that the naïve T-cell compartment is drained by a high rate of mature naïve cell loss in the periphery due to bystander apoptosis or activation-induced differentiation. X4 viruses could play a role in the depletion of naïve T cells in poor immunological responders to HAART by triggering persistent T-cell activation and bystander apoptosis via gp120-CXCR4 interactions.

10.1128/jvi.00965-06

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Citations (58)

Th22 cells are efficiently recruited in the gut by CCL28 as an alternative to CCL20 but do not compensate for the loss of Th17 cells in treated HIV-1-infected individuals

Mucosal Immunology (2020)

Manon Nayrac Mary Réquena Claire Loiseau Michelle Cazabat Bertrand Suc

CCL20

10.1038/s41385-020-0286-6

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Citations (9)

Brief Report: HIV-1 Tropism During Primary Infections in France: 1996–2014

JAIDS Journal of Acquired Immune Deficiency Syndromes (2016)

Stéphanie Raymond Florence Nicot Karine Sauné Michelle Cazabat Christophe Pasquier

HIV-1 was mainly CCR5 tropic in recent seroconverters. We analyzed the coreceptor use in 239 primary HIV-1 infections (PHIs) between 1996 and 2014 using a validated recombinant virus phenotypic entry assay. CXCR4-using viruses were detected in 8.3%, 3.8%, and 6.1% of PHIs from 1996 to 2004, 2005 to 2009, and 2010 to 2014, respectively. The presence of CXCR4-using viruses was associated with the virological failure of antiretroviral treatment initiated during PHI (odds ratio, 7.9; 95% confidence interval, 1.1 to 56.5). The phenotypic tropism assay data show that the prevalence of X4 tropic transmitted viruses was stable in this French cohort of PHIs between 1996 and 2014.

Tissue tropism

Maraviroc

10.1097/qai.0000000000000984

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Citations (5)

Persistence of distinct HIV-1 populations in blood monocytes and naive and memory CD4 T cells during prolonged suppressive HAART

AIDS (2005)

Pierre Delobel Karine Sauné Michelle Cazabat F. L'Faqihi Christian Aquilina

Objective: Reservoirs of HIV-1 are a major obstacle to virus eradication. There is therefore a need to clearly understand the molecular nature of the virus populations that persist in patients with sustained suppression of plasma viraemia on highly active antiretroviral therapy (HAART). Design: We performed a detailed analysis of the genotypes of HIV-1 quasispecies isolated from highly purified blood cell types taken from three selected patients with sustained undetectable viral loads on HAART for 7 years. Methods: We used polychromatic flow cytometry to sort naive and memory CD4 T cells, CD14 monocytes, and CD56+CD3− natural killer (NK) cells from the total peripheral blood mononuclear cells after 7 years of HAART. Clonal analysis was used to determine coreceptor use and drug-resistance genotypes of HIV-1 quasispecies in the sorted blood cell types. Results: We detected HIV-1 DNA in memory and naive CD4 T cells and in CD14 monocytes, but not in the CD56+CD3− NK cells. Phylogenetic analysis demonstrated that the various blood cells types of two of the three patients harboured genetically distinct HIV-1 quasispecies. Drug-resistance mutations were also distributed differently from one cell type to another. This compartmentalization suggests a minimal virus trafficking between blood cell types during suppressive HAART. Conclusions: We observed a cell-specific compartmentalization of the residual virus populations during prolonged suppressive HAART. The coexistence of numerous HIV-1 quasispecies with different resistance genotypes and coreceptor use in cellular reservoirs may be relevant for future antiretroviral treatment strategies.

Viral quasispecies

10.1097/01.aids.0000183125.93958.26

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Citations (83)

CCR6− regulatory T cells blunt the restoration of gut Th17 cells along the CCR6–CCL20 axis in treated HIV-1-infected individuals

Mucosal Immunology (2016)

Claire Loiseau Mary Réquena Maud Mavigner Michelle Cazabat Nicolas Carrère

CCL20

Homing (biology)

10.1038/mi.2016.7

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Citations (37)

Population-Based Sequencing of the V3 Region of env for Predicting the Coreceptor Usage of Human Immunodeficiency Virus Type 1 Quasispecies

Journal of Clinical Microbiology (2007)

Pierre Delobel Marie-Thérèse Nugeyre Michelle Cazabat Christophe Pasquier B. Marchou

ABSTRACT Genotypic population-based methods could be faster and less expensive than phenotypic recombinant assays for determining human immunodeficiency virus type 1 (HIV-1) coreceptor usage in patient samples, but their clinical use requires good genotype-phenotype correlation and concordance with clonal analyses. We have assessed these requirements by clonal analysis of the V1 to V3 env PCR products of 26 patients infected with subtype B HIV-1. We used the resulting set of molecular clones, all sequenced and characterized using a single-cycle recombinant virus phenotypic entry assay, to reevaluate genotype-phenotype correlations. Combining the previously described 11/25 and net charge rules for the V3 genotype improved the prediction of HIV-1 coreceptor usage. We also evaluated the concordance of population-based and clonal analyses for predicting the coreceptor usage of HIV-1 quasispecies. Our population-based recombinant phenotypic assay and direct sequencing of V3 were similarly sensitive for detecting the presence of minor species in the virus population, and both correlated well with clonal analysis. The improved genotype-phenotype correlation obtained by combining two simple genotypic rules and the good concordance with clonal analyses suggest that direct sequencing of V3 is a valuable alternative to population-based recombinant phenotypic assays.

Viral quasispecies

Concordance

Subtyping

10.1128/jcm.02090-06

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Citations (82)

THETA: a new genotypic approach for predicting HIV-1 CRF02-AG coreceptor usage

Bioinformatics (2019)

Chloé Dimeglio Stéphanie Raymond Nicolas Jeanne Christelle Reynès Romain Carcenac

Abstract Motivation The circulating recombinant form of HIV-1 CRF02-AG is the most frequent non-B subtype in Europe. Anti-HIV therapy and pathophysiological studies on the impact of HIV-1 tropism require genotypic determination of HIV-1 tropism for non-B subtypes. But genotypic approaches based on analysis of the V3 envelope region perform poorly when used to determine the tropism of CRF02-AG. We, therefore, designed an algorithm based on information from the gp120 and gp41 ectodomain that better predicts the tropism of HIV-1 subtype CRF02-AG. Results We used a bio-statistical method to identify the genotypic determinants of CRF02-AG coreceptor use. Toulouse HIV Extended Tropism Algorithm (THETA), based on a Least Absolute Shrinkage and Selection Operator method, uses HIV envelope sequence from phenotypically characterized clones. Prediction of R5X4/X4 viruses was 86% sensitive and that of R5 viruses was 89% specific with our model. The overall accuracy of THETA was 88%, making it sufficiently reliable for predicting the tropism of subtype CRF02-AG sequences. Availability and implementation Binaries are freely available for download at https://github.com/viro-tls/THETA. It was implemented in Matlab and supported on MS Windows platform. The sequence data used in this work are available from GenBank under the accession numbers MK618182-MK618417.

Maraviroc

10.1093/bioinformatics/btz585

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Citations (4)

T regulatory cells disrupt the CCL20-CCR6 axis driving Th17 homing to the gut

Claire Loiseau Mary Réquena Michelle Cazabat Nicolas Carrère Bertrand Suc

Background: During HIV-1 infection, the integrity of the intestinal immune barrier is disrupted due to a deep depletion of CD4 + T cells in the gut. The translocation of microbial products from the gut lumen into the bloodstream has been linked with systemic inflammation. Despite long-term effective cART, CD4 + T cells in the lamina propria are incompletely restored in most individuals. Aims: Among the chemotactic axes involved in CD4 + T cell homing to the gut, we focused on the CCR6-CCL20 axis as it governs Th17 cells homing, a T cell subset exerting a major role in antimicrobial immunity. We aimed to assess the factors regulating the expression of CCL20 by the enterocytes, and notably the role of the cytokines produced by Treg and Th17 cells. Methods: Small bowel biopsies were obtained by endoscopy in 20 HIV-1 + and 10 HIV-1-individuals. Intestinal lymphocytes phenotype was analyzed by flow cytometry. CCL20 mRNA was quantified by qRT-PCR. The effect of PRR ligands and cytokines on CCL20 expression was explored using an ex-vivosystem of human primary enterocytes. A coculture was done between the enterocytes and Th17/Treg cells. The expression of CCL20 by the enterocytes was evaluated by qRT-PCR and ELISA.

CCL20

Homing (biology)

Lamina propria

Caco-2

Source

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Citations (0)

Platelets from HIV-infected individuals on antiretroviral drug therapy with poor CD4 + T cell recovery can harbor replication-competent HIV despite viral suppression

HAL (Le Centre pour la Communication Scientifique Directe) (2020)

Fernando Real Claude Capron Alexis Sennepin Riccardo Arrigucci Aiwei Zhu

Replication

Drug holiday

10.1126/scitranslmed.aat626

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Citations (4)

Quantification of HEV RNA by Droplet Digital PCR

Viruses (2016)

Florence Nicot Michelle Cazabat Sébastien Lhomme Olivier Marion Karine Sauné

The sensitivity of real-time PCR for hepatitis E virus (HEV) RNA quantification differs greatly among techniques. Standardized tools that measure the real quantity of virus are needed. We assessed the performance of a reverse transcription droplet digital PCR (RT-ddPCR) assay that gives absolute quantities of HEV RNA. Analytical and clinical validation was done on HEV genotypes 1, 3 and 4, and was based on open reading frame (ORF)3 amplification. The within-run and between-run reproducibilities were very good, the analytical sensitivity was 80 HEV RNA international units (IU)/mL and linearities of HEV genotype 1, 3 and 4 were very similar. Clinical validation based on 45 samples of genotype 1, 3 or 4 gave results that correlated well with a validated reverse transcription quantitative PCR (RT-qPCR) assay (Spearman rs = 0.89, p < 0.0001). The RT-ddPCR assay is a sensitive method and could be a promising tool for standardizing HEV RNA quantification in various sample types.

Hepatitis E Virus

10.3390/v8080233

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Citations (30)