Laboratoire Associe Au Center National Of Reference Du Vih

Sotteville-lès-Rouen, France

Laboratoire Associe Au Center National Of Reference Du Vih

Sotteville-lès-Rouen, France
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Sauter D.,University of Ulm | Hotter D.,University of Ulm | Van Driessche B.,Free University of Brussels | Sturzel C.M.,University of Ulm | And 10 more authors.
Cell Reports | Year: 2015

NF-κB is essential for effective transcription of primate lentiviral genomes and also activates antiviral host genes. Here, we show that the early protein Nef of most primate lentiviruses enhances NF-κB activation. In contrast, the late protein Vpu of HIV-1 and its simian precursors inhibits activation of NF-κB, even in the presence of Nef. Although this effect of Vpu did not correlate with its ability to interact withβ-TrCP, it involved the stabilization of IκB and reduced nuclear translocation of p65. Interestingly, however, Vpu did not affect casein kinase II-mediated phosphorylation of p65. Lack of Vpu was associated with increased NF-κB activation and induction of interferon and interferon-stimulated genes (ISGs) in HIV-1-infected Tcells. Thus, HIV-1 and its simian precursors employ Nef to boost NF-κB activation early during the viral life cycle to initiate proviral transcription, while Vpu is used to downmodulate NF-κB-dependent expression of ISGs at later stages. © 2015 The Authors.


Depatureaux A.,Laboratoire Associe Au Center National Of Reference Du Vih | Charpentier C.,Laboratoire Associe Au Center National Of Reference Du Vih | Collin G.,Laboratoire Of Virologie | Leoz M.,Laboratoire Associe Au Center National Of Reference Du Vih | And 6 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2010

We assessed the natural genotypic and phenotypic susceptibilities to enfuvirtide of 171 HIV group O (HIV-O) samples and 29 strains, respectively. The N42D resistance-associated mutation in the gp41 region was detected in 98% of cases. The phenotypic assay showed a wide range of baseline susceptibilities, with 50% inhibitory concentrations (IC50s) from 4 to 5,000 nM, a range similar to that reported for HIV-1 group M. Thus, despite the natural genotypic resistance conferred by the N42D signature mutation, HIV-O variants appear to be phenotypically susceptible. Enfuvirtide could therefore potentially be used in antiretroviral treatments for HIV-O-infected patients. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Leoz M.,Laboratoire Of Virologie | Leoz M.,University of Rouen | Feyertag F.,University of Manchester | Kfutwah A.,Center Pasteur du Cameroun | And 11 more authors.
PLoS Pathogens | Year: 2015

Unlike the pandemic form of HIV-1 (group M), group O viruses are endemic in west central Africa, especially in Cameroon. However, little is known about group O’s genetic evolution, and why this highly divergent lineage has not become pandemic. Using a unique and large set of group O sequences from samples collected from 1987 to 2012, we find that this lineage has evolved in successive slow and fast phases of diversification, with a most recent common ancestor estimated to have existed around 1930 (1914–1944). The most rapid periods of diversification occurred in the 1950s and in the 1980s, and could be linked to favourable epidemiological contexts in Cameroon. Group O genetic diversity reflects this two-phase evolution, with two distinct populations potentially having different viral properties. The currently predominant viral population emerged in the 1980s, from an ancient population which had first developed in the 1950s, and is characterized by higher growth and evolutionary rates, and the natural presence of the Y181C resistance mutation, thought to confer a phenotypic advantage. Our findings show that although this evolutionary pattern is specific to HIV-1 group O, it paralleled the early spread of HIV-1 group M in the Democratic Republic of Congo. Both viral lineages are likely to have benefited from similar epidemiological contexts. The relative role of virological and social factors in the distinct epidemic histories of HIV-1 group O and M needs to be reassessed. © 2015 Leoz et al.


Mourez T.,University Of Normandie | Mourez T.,University of Rouen | Mourez T.,Laboratoire Associe Au Center National Of Reference Du Vih | Simon F.,University Paris Diderot | And 4 more authors.
Clinical Microbiology Reviews | Year: 2013

The AIDS pandemic that started in the early 1980s is due to human immunodeficiency virus type 1 (HIV-1) groupM(HIV-M), but apart from this major group, many divergent variants have been described (HIV-1 groups N, O, and P and HIV-2). The four HIV-1 groups arose from independent cross-species transmission of the simian immunodeficiency viruses (SIVs) SIVcpz, infecting chimpanzees, and SIVgor, infecting gorillas. This, together with human adaptation, accounts for their genomic, phylogenetic, and virological specificities. Nevertheless, the natural course of non-M HIV infection seems similar to that of HIV-M. The virological monitoring of infected patients is now possible with commercial kits, but their therapeutic management remains complex. All non-M variants were principally described for patients linked to Cameroon, where HIV-O accounts for 1% of all HIV infections; only 15 cases of HIV-N infection and 2 HIV-P infections have been reported. Despite improvements in our knowledge, many fascinating questions remain concerning the origin, genetic evolution, and slow spread of these variants. Other variants may already exist or may arise in the future, calling for close surveillance. This review provides a comprehensive, up-to-date summary of the current knowledge on these pathogens, including the historical background of their discovery; the latest advances in the comprehension of their origin and spread; and clinical, therapeutic, and laboratory aspects that may be useful for the management and the treatment of patients infected with these divergent viruses. © 2013, American Society for Microbiology. All Rights Reserved.


Gueudin M.,Laboratoire Associe Au Center National Of Reference Du Vih | Gueudin M.,University of Rouen | Leoz M.,Laboratoire Associe Au Center National Of Reference Du Vih | Leoz M.,University of Rouen | And 6 more authors.
Journal of Clinical Microbiology | Year: 2012

The correct diagnosis and monitoring of HIV-1 group O (HIV-O) infection are essential for appropriate patient management, for the prevention of mother-to-child transmission, and for the detection of dual HIV-M/HIV-O infections. HIV-O RNA quantification is currently possible with two commercial kits (from Abbott and Roche), which quantify HIV-M and HIV-O strains indifferently; therefore, they cannot be used for the specific identification of HIV-O infection. We designed a new real-time quantitative reverse transcription PCR (RT-qPCR assay) (INT-O), which we compared with our previous version, LTR-O, and with the Abbott RealTime HIV-1 kit. Specificity was assessed with 27 HIV-1 group M strains and the prototype strain of group P. Clinical performances were analyzed by using 198 stored plasma samples, representative of HIV-O genetic diversity. Analytical sensitivity, repeatability, and reproducibility were also determined. The detection limit of the INT-O assay was 40 copies/ml, and its specificity was 100%. The repeatability and reproducibility were excellent. Analysis of clinical samples showed a good correlation between the INT-O and LTR-O assays (r = 0.8240), with an improvement of analytical sensitivity. A good correlation was also obtained between the INT-O and Abbott assays (r = 0.8599) but with significantly higher values (0.19 logs) for the INT-O method, due to marked underquantifications for some patients. These results showed that HIV-O genetic diversity still has an impact on RNA quantification. The new assay, INT-O, allows both the specific diagnosis of HIV-O infection and the quantification of diverse HIV-O strains. Its detection limit is equivalent to that of commercial kits. This assay is cheap and suitable for use in areas in which strains of HIV-1 groups M and O cocirculate. Copyright © 2012, American Society for Microbiology. All Rights Reserved.


Vessiere A.,Center Pasteur du Cameroun | Rousset D.,Center Pasteur du Cameroun | Kfutwah A.,Center Pasteur du Cameroun | Leoz M.,Center Pasteur du Cameroun | And 3 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2010

OBJECTIVE: To define a routine algorithm for the specific diagnosis and complete follow-up of HIV-1 group O (HIV-O) infections in Cameroun. METHODS: During 18 months, samples referred to Centre Pasteur du Cameroun for HIV testing or viral monitoring were screened for HIV-O infection with an in-house serotyping assay. HIV-O viral load was quantified by real-time polymerase chain reaction in the LTR gene and resistance genotyping was performed on pol and env sequences. RESULTS: Of the 7030 samples tested, 78 HIV-O infections (1.1%) were identified, including 7 M and O dually seroreactive samples (9%). All treatment-naive patients and 59% of the patients receiving HAART had detectable viral loads. Analysis of pol sequences from 15 treatment-naive patients revealed a high number of polymorphisms in the protease region, with natural residues implicated in genotypic resistance to tipranavir and saquinavir for HIV-1 group M according to the Agence Nationale de Recherches sur le Sida et les Hépatites virales algorithm. Six patients (40%) harbored the 181C mutation conferring natural resistance to nonnucleoside reverse transcriptase inhibitors. Among antiretroviral-treated patients, major resistance mutations described for HIV-1 group M were found. CONCLUSIONS: HIV-O prevalence remains relatively low in Cameroun. The cocirculation of groups M and O in this country leads to replicative dual infections. HIV-O-infected patients in this region can now benefit from effective and specific tools for a complete monitoring of infection. However, further studies are needed to understand long-term response to antiretrovirals of these complex variants. Copyright © 2009 by Lippincott Williams & Wilkins.


PubMed | Membre du Reseau International des Institute Pasteur and Laboratoire Associe Au Center National Of Reference Du Vih
Type: | Journal: Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology | Year: 2013

Fourth generation assays for HIV diagnosis are progressively being introduced into routine services, due to their improvement of diagnosis. In spite of this, HIV diagnosis remains a challenge in sub-Saharan Africa, due to false positive reactivity. There is a continuous need for field evaluations and routine validations of fourth generation HIV tests in African populations.Evaluate the performances of the ARCHITECT HIV Ag/Ab kit (Abbott) in a population living in an African setting-Cameroon compared to a population living in a European setting-France.645 HIV samples from both France and Cameroon were evaluated. The positive panel (378 samples) included a diverse series of HIV-1 variants (groups M, N, O, and P) as well as HIV-2 samples. Results were compared to original diagnosis done with other 4th generation assays (AxSYM HIV Ag/Ab (Abbott) and Vidas HIV DUO QUICK) (bioMrieux).Sensitivity of the ARCHITECT was 100% in both sites. It diagnosed all variants of the panel with different reactivity profiles following strain diversity. A wider range of reactivity was observed for group O. Specificity was slightly lower (97.6%) in Cameroon than in France (98.6%), probably due to a higher rate of false positive reactivity. ARCHITECT HIV Ag/Ab assay had high performances in clinical sensitivity and specificity and is adapted to the wide genetic diversity of viruses circulating in West Central Africa.Our results further highlight the need to evaluate HIV diagnostic tests before introduction into routine diagnostic services both in the North and in the South.


Depatureaux A.,Lady Davis Institute for Medical Research | Quashie P.K.,Lady Davis Institute for Medical Research | Mesplede T.,Lady Davis Institute for Medical Research | Han Y.,Lady Davis Institute for Medical Research | And 6 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014

HIV-1 group O (HIV-O) is a rare HIV-1 variant characterized by a high number of polymorphisms, especially in the integrase coding region. As HIV-O integrase enzymes have not previously been studied, our aim was to assess the impact of HIV-O integrase polymorphisms on enzyme function and susceptibility to integrase inhibitors. Accordingly, we cloned and purified integrase proteins from each of HIV-1 group O clades A and B, an HIV-O divergent strain, and HIV-1 group M (HIV-M, subtype B), used as a reference. To assess enzymatic function of HIV-O integrase, we carried out strand transfer and 3 = processing assays with various concentrations of substrate (DNA target and long terminal repeats [LTR], respectively) and characterized these enzymes for susceptibility to integrase strand transfer inhibitors (INSTIs) in cell-free assays and in tissue culture, in the absence or presence of various concentrations of several INSTIs. The inhibition constant (Ki) and 50% effective concentration ( EC 50 ) values were calculated for HIV-O integrases and HIV-O viruses, respectively, and compared with those of HIV-M. The results showed that HIV-O integrase displayed lower activity in strand transfer assays than did HIV-M enzyme, whereas 3= processing activities were similar to those of HIV-M. HIV-O integrases were more susceptible to raltegravir (RAL) in competitive inhibition assays and in tissue culture than were HIV-M enzymes and viruses, respectively. Molecular modeling suggests that two key polymorphic residues that are close to the integrase catalytic site, 74I and 153A, may play a role in these differences. Copyright © 2014 American Society for Microbiology. All Rights Reserved.


Kfutwah A.,Membre du Reseau International des Institute Pasteur Yaounde | Lemee V.,Laboratoire Associe Au Center National Of Reference Du Vih | Ngono H.V.,Membre du Reseau International des Institute Pasteur Yaounde | De Oliveira F.,Laboratoire Associe Au Center National Of Reference Du Vih | And 2 more authors.
Journal of Clinical Virology | Year: 2013

Background: Fourth generation assays for HIV diagnosis are progressively being introduced into routine services, due to their improvement of diagnosis. In spite of this, HIV diagnosis remains a challenge in sub-Saharan Africa, due to false positive reactivity. There is a continuous need for field evaluations and routine validations of fourth generation HIV tests in African populations. Objectives: Evaluate the performances of the ARCHITECT HIV Ag/Ab kit (Abbott) in a population living in an African setting-Cameroon compared to a population living in a European setting-France. Study design: 645 HIV samples from both France and Cameroon were evaluated. The positive panel (378 samples) included a diverse series of HIV-1 variants (groups M, N, O, and P) as well as HIV-2 samples. Results were compared to original diagnosis done with other 4th generation assays (AxSYM HIV Ag/Ab (Abbott) and Vidas HIV DUO QUICK) (bioMérieux). Results: Sensitivity of the ARCHITECT was 100% in both sites. It diagnosed all variants of the panel with different reactivity profiles following strain diversity. A wider range of reactivity was observed for group O. Specificity was slightly lower (97.6%) in Cameroon than in France (98.6%), probably due to a higher rate of false positive reactivity. ARCHITECT HIV Ag/Ab assay had high performances in clinical sensitivity and specificity and is adapted to the wide genetic diversity of viruses circulating in West Central Africa. Conclusion: Our results further highlight the need to evaluate HIV diagnostic tests before introduction into routine diagnostic services both in the North and in the South. © 2013 Elsevier B.V.


Depatureaux A.,Lady Davis Institute for Medical Research | Mesplede T.,Lady Davis Institute for Medical Research | Quashie P.,Lady Davis Institute for Medical Research | Oliveira M.,Lady Davis Institute for Medical Research | And 4 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2015

Background: HIV-1 group O (HIV-O) is a rare variant that is characterized by a high number of natural polymorphisms in the integrase coding region that may impact on susceptibility to integrase strand transfer inhibitors (INSTIs) and on the emergence of resistance substitutions. We previously reported that HIV-O is more susceptible to RAL than HIV-1 group M (HIV-M). Methods: The aim of this study was to assess pathways of resistance to INSTIs in group 0 variants. Accordingly, we selected for resistance to each of raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) in cord blood mononuclear cells using HIV group O subtypes A and B, an HIV-O divergent isolate, and HIV-1 group M (subtype B, which served as a reference). Site-directed mutagenesis was performed on the pCOM2.5 HIV group 0 infectious clone to ascertain the impact of INSTI resistance substitutions at positions Q148R, N155H, and R263K within integrase on susceptibility to INSTIs and infectiousness. Results: Cell culture selections of group O variants yielded similar patterns of resistance to RAL, EVG, and DTG as observed for subtype B. In the DTG selections, subtype B yielded S153Y, whereas a natural S153A polymorphism sometimes led to A153V in group O. The pCMO2.5/Q148R and pCMO2.5/N155H variants displayed far higher levels of resistance to DTG (>1000 FC) than was seen for group M viruses. Conclusions: HIV-O harboring Q148R and N155H shows higher resistance to DTG compared with HIV-M subtype B. © 2015 Wolters Kluwer Health, Inc.

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