Expertise

Hub members Have many expertise, covering most of the fields in bioinformatics and biostatistics. You'll find below a non-exhaustive list of these expertise

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Searched keyword : Virus

Related people (3)

Thomas BIGOT

Group : GIPHY - Embedded : Biology of Infection

I joined the C3BI Hub in 2016 after a curriculum widely dedicated to Bioinformatics studies, and more precisely to Phylogeny and Evolution, topics of my PhD thesis. At Institut Pasteur, I am involved in projects dealing with sequences homology : alignments, hmm profiles, making homologous family databases, kmers signatures. I am also a developer (Python / C++) with a solid interest in optimization as well as in developing usable tools for final user such as automated pipeline for metagenomics sequence analysis. I’m currently embedded in Marc Eloit’s team (80% of my work time). My main task in this team is to develop strategies to identify, in their metagenomics samples, new pathogens, or new combination pathogen / symptoms. The rest of my time, I manage small projects and participate to the Hub life. I am currently experimenting with functional programming (for now, using Python) and its applicability to bioinformatics issues.


Keywords
AlgorithmicsScientific computingSofware development and engineeringParallel computingGraph theory and analysis
Organisms
BacteriaFungiVirus
Projects (5)

Julien GUGLIELMINI


After a PhD in Microbiology on bacterial toxin-antitoxin systems at the Free University of Brussels, I joined the Institut Pasteur for a 3 years postdoc in Eduardo Rocha’s lab. During this period, I performed comparative genomics and pylogenetic analysis on bacterial conjugation and type IV secretion systems. Then, I worked 2 years in Olivier Tenaillon’s team on the modelling and evolution of organismal complexity. I joined the HUB in 2015, and I am involved in phylogenetic and comparative genomics projects.


Keywords
GenomicsPhylogeneticsSequence analysisGenome analysisGeneticsEvolutionPopulation genetics
Organisms
ArchaeaBacteriaVirus
Projects (10)

Related projects (89)

Regulation of HIV replication by cellular DNA topology

HIV-1 replication requires the integration of the viral genome into the cell genome. A viral-encoded enzyme, integrase (IN), performs this critical step of infection and is a promising target for anti-viral therapeutics. If the catalytic properties of INs are well characterized, the mechanisms responsible for their site selectivity are still under investigation. Several cellular proteins, such as the LEDFGF/p75 transcription regulator, the RNA polymerase II machinery, nuclear pore proteins and specific modified histones have been proposed to be involved in IN selectivity at a genomic level. In addition, structural parameters of the target DNA helix (curvature, flexibility and topology) are proposed to regulate IN selectivity at a local level. Our team is studying the role and molecular mechanisms associated with these various parameters (Botbol et al., 2008; Lesbats et al., 2011; Morchikh et al., 2013; Benleulmi et al., 2015; Naughtin et al.,). This project aims to define the role of cellular DNA topology during HIV-1 integration. We will first compare already mapped integration sites and superhelicity profiles and search for possible correlations between these two parameters. We will then modify topoisomerases activity in infected cells and study the consequences on viral replication and integration. Finally, we will study in vitro, the direct effects on integration of two parameters of DNA topology, the twist and writhe of the DNA helix. This project relies on complementary in vivo, in vitro and in silico approaches. Bio-informatics tools are crucial for the correlative and statistical analyses of integration sites and superhelicity maps.



Project status : Declined

Regulation of HIV replication by cellular DNA topology

HIV-1 replication requires the integration of the viral genome into the cell genome. A viral-encoded enzyme, integrase (IN), performs this critical step of infection and is a promising target for anti-viral therapeutics. If the catalytic properties of INs are well characterized, the mechanisms responsible for their site selectivity are still under investigation. Several cellular proteins, such as the LEDFGF/p75 transcription regulator, the RNA polymerase II machinery, nuclear pore proteins and specific modified histones have been proposed to be involved in IN selectivity at a genomic level. In addition, structural parameters of the target DNA helix (curvature, flexibility and topology) are proposed to regulate IN selectivity at a local level. Our team is studying the role and molecular mechanisms associated with these various parameters (Botbol et al., 2008; Lesbats et al., 2011; Morchikh et al., 2013; Benleulmi et al., 2015; Naughtin et al.,). This project aims to define the role of cellular DNA topology during HIV-1 integration. We will first compare already mapped integration sites and superhelicity profiles and search for possible correlations between these two parameters. We will then modify topoisomerases activity in infected cells and study the consequences on viral replication and integration. Finally, we will study in vitro, the direct effects on integration of two parameters of DNA topology, the twist and writhe of the DNA helix. This project relies on complementary in vivo, in vitro and in silico approaches. Bio-informatics tools are crucial for the correlative and statistical analyses of integration sites and superhelicity maps.



Project status : Declined

Evolutionary relationships between giant viruses and eukaryotes

The phylogenetic position and status of “giant viruses”, formerly called NucleoCytoplasmic Large DNA viruses (NCLDV) or putative order Megavirales, are controversial. Many preliminary phylogenetic analyses have been published, but their presentations are usually highly biased by the prejudice of the authors concerning the nature of giant viruses. Our own preliminary analyses suggest that giant viruses are indeed ancient (they predate the last universal eukaryotic ancestor) and have possibly provided important functions to emerging eukaryotic cells (e.g. DNA topoisomerase activities). The number of giant virus genomes has recently dramatically increased, opening new opportunity to study their position in the “universal tree of life” and their evolutionary relationships with eukaryotes. The aim of the project is to perform an exhaustive phylogenetic analysis of all giant virus proteins with eukaryotic (archaeal/bacterial) homologues to (i) test the monophyly of giant viruses, (ii) determine their contribution to early eukaryotic evolution, iii) determine if some giant virus proteins can be useful to root the eukaryotic tree. We need the help of a bioinformatics colleague with good expertise in building phylogenetic trees from large data sets using different methods of tree construction and robustness evaluation. This work will be complemented by the systematic search for significant indels (insertion/deletion) in the alignments obtained by two members of the BMGE team (Patrick Forterre and Morgan Gaia).



Project status : In Progress

viral evolution around Ebola Treatment Centre in Macenta and according to disease outcomes

The 2013-2015 Ebola virus disease epidemic is the largest outbreak so far described with 27 305 cases and 11 169 deaths. The virus spread by human to human contact throughout Western Africa and never before has a variant been transmitted for such a sustained period of time. Ebola virus are RNA virus so as other RNA viruses they could accumulate mutations during evolution. Therefore it is an emergency to monitor viral changes and adaptation within and between individuals in order to help researchers to better understand susceptibility to Ebola infections, to guide research on therapeutic targets and to ensure accurate diagnosis. New technologies can provide information about pathogen’s evolution and in our lab we have access to an Ion PGMTM sequencer. Thanks to the national reference center for viral hemorrhagic fever (VHF) we have at our disposal a large number of samples collected from Ebola infected patients especially from Guinea. We have developed an Amplicon approach using sixteen couples of specific primers for Ebola viruses and a RNA sequencing method based on randomly primed cDNA synthesis to product our libraries. Ion PGMTM Hi-Q sequencing kit will be used to sequence up to 400 bp inserts loaded onto 316v2TM or 318v2TM chip. Through high depth sequencing we would like to follow up the profiling of intra and inter host viral quasispecies at different time of the epidemic in the geographic area of the Ebola Treatment Centre in Macenta. Thanks to the activities of national reference center for VHF and the Biomics Pole one aim of the project is also to occasionally compare viral quasispecies and consensus sequences between patients who get uncommon symptoms from those who get classical illness and to study intra host quasispecies in different biological fluids (cerebrospinal fluid, sperm, urine) to see if there are differences between persistent species and viral quasispecies found during symptomatic step.



Project status : Closed

viral evolution around Ebola Treatment Centre in Macenta and according to disease outcomes

The 2013-2015 Ebola virus disease epidemic is the largest outbreak so far described with 27 305 cases and 11 169 deaths. The virus spread by human to human contact throughout Western Africa and never before has a variant been transmitted for such a sustained period of time. Ebola virus are RNA virus so as other RNA viruses they could accumulate mutations during evolution. Therefore it is an emergency to monitor viral changes and adaptation within and between individuals in order to help researchers to better understand susceptibility to Ebola infections, to guide research on therapeutic targets and to ensure accurate diagnosis. New technologies can provide information about pathogen’s evolution and in our lab we have access to an Ion PGMTM sequencer. Thanks to the national reference center for viral hemorrhagic fever (VHF) we have at our disposal a large number of samples collected from Ebola infected patients especially from Guinea. We have developed an Amplicon approach using sixteen couples of specific primers for Ebola viruses and a RNA sequencing method based on randomly primed cDNA synthesis to product our libraries. Ion PGMTM Hi-Q sequencing kit will be used to sequence up to 400 bp inserts loaded onto 316v2TM or 318v2TM chip. Through high depth sequencing we would like to follow up the profiling of intra and inter host viral quasispecies at different time of the epidemic in the geographic area of the Ebola Treatment Centre in Macenta. Thanks to the activities of national reference center for VHF and the Biomics Pole one aim of the project is also to occasionally compare viral quasispecies and consensus sequences between patients who get uncommon symptoms from those who get classical illness and to study intra host quasispecies in different biological fluids (cerebrospinal fluid, sperm, urine) to see if there are differences between persistent species and viral quasispecies found during symptomatic step.



Project status : Closed

Identification of new cellular parameters involved in HIV-1 integration selectivity

HIV-1 replication requires the integration of the viral genome into the cell genome. A viral-encoded enzyme, integrase (IN), performs this critical step of infection and is a promising target for anti-viral therapeutics. If the catalytic properties of INs are well characterized, the mechanisms responsible for their site selectivity are still under investigation. Several cellular proteins, such as the LEDFGF/p75 transcription co-activator, the RNA polymerase II machinery, nuclear pore proteins and specific modified histones have been proposed to be involved in IN selectivity at a genomic level but the underlying molecular mechanisms remain to be demonstrated. In addition, structural parameters of the target DNA helix (curvature, flexibility, topology) are proposed to regulate IN selectivity at a local level. Our aims are to study the role of these different parameters of IN selectivity, using both in vitro and in vivo approaches. In vitro, we will map integration sites on various target DNA substrates (naked DNA or chromatin, minicircles, plasmids with different topologies, transcribed templates) and will test the effect of purified proteins suspected to regulate IN selectivity. In vivo, integration sites will be mapped in cells depleted of these suspected regulators or in cells incubated with drugs targeting enzymes involved in transcription, DNA topology or histone modifications. Integration sites will be mapped using published or “home-made” protocols and the sites will be compared with DNA structural parameters, nucleosome positions, histone modifications or transcriptional parameters (published maps). Bio-informatics tools are crucial for these correlative and statistical analyses of integration sites. Our project relies on complementary in vivo, in vitro and in silico approaches. It should establish molecular and mechanistic rules of HIV-1 integration selectivity that could serve in the development of new antiviral strategies and of safer gene therapy vectors.



Project status : Closed

Identification of new cellular parameters involved in HIV-1 integration selectivity

HIV-1 replication requires the integration of the viral genome into the cell genome. A viral-encoded enzyme, integrase (IN), performs this critical step of infection and is a promising target for anti-viral therapeutics. If the catalytic properties of INs are well characterized, the mechanisms responsible for their site selectivity are still under investigation. Several cellular proteins, such as the LEDFGF/p75 transcription co-activator, the RNA polymerase II machinery, nuclear pore proteins and specific modified histones have been proposed to be involved in IN selectivity at a genomic level but the underlying molecular mechanisms remain to be demonstrated. In addition, structural parameters of the target DNA helix (curvature, flexibility, topology) are proposed to regulate IN selectivity at a local level. Our aims are to study the role of these different parameters of IN selectivity, using both in vitro and in vivo approaches. In vitro, we will map integration sites on various target DNA substrates (naked DNA or chromatin, minicircles, plasmids with different topologies, transcribed templates) and will test the effect of purified proteins suspected to regulate IN selectivity. In vivo, integration sites will be mapped in cells depleted of these suspected regulators or in cells incubated with drugs targeting enzymes involved in transcription, DNA topology or histone modifications. Integration sites will be mapped using published or “home-made” protocols and the sites will be compared with DNA structural parameters, nucleosome positions, histone modifications or transcriptional parameters (published maps). Bio-informatics tools are crucial for these correlative and statistical analyses of integration sites. Our project relies on complementary in vivo, in vitro and in silico approaches. It should establish molecular and mechanistic rules of HIV-1 integration selectivity that could serve in the development of new antiviral strategies and of safer gene therapy vectors.



Project status : Closed

A reference panel of dengue vector genomes

Dengue prevention relies primarily on controlling populations of the main mosquito vector, Aedes aegypti, which is failing in many parts of the world because of the lack of sustained commitment of resources and ineffective implementation. Novel entomological approaches to dengue control are being developed that aim at replacing or suppressing mosquito vector populations. Insufficient genomic resources for Ae. aegypti, however, have until now impeded progress in both basic and applied research on this medically important mosquito species. The only available reference genome for Ae. aegypti is a draft that consists of over 4,800 unassembled fragments with incomplete annotation. Moreover, the inbred Ae. aegypti laboratory strain that was sequenced does not universally represent the considerable genetic and ecological diversity of the species worldwide. The large size of the genome and its high content in repeat-rich sequences of transposable elements was a major difficulty to assemble the Ae. aegypti genome sequence. In the present project, we aim to overcome this difficulty using a novel strategy for genome sequencing and assembly. The ultimate goal is to produce several, fully assembled, well-annotated, new Ae. aegypti reference genomes from epidemiologically relevant populations. The expected outcome is a genome reference panel including a catalog of species-wide genetic variation that will significantly improve genomic resources for Ae. aegypti research and help address a broad range of biological questions related to Ae. aegypti vectorial capacity and dengue virus transmission.



Project status : Closed

A reference panel of dengue vector genomes

Dengue prevention relies primarily on controlling populations of the main mosquito vector, Aedes aegypti, which is failing in many parts of the world because of the lack of sustained commitment of resources and ineffective implementation. Novel entomological approaches to dengue control are being developed that aim at replacing or suppressing mosquito vector populations. Insufficient genomic resources for Ae. aegypti, however, have until now impeded progress in both basic and applied research on this medically important mosquito species. The only available reference genome for Ae. aegypti is a draft that consists of over 4,800 unassembled fragments with incomplete annotation. Moreover, the inbred Ae. aegypti laboratory strain that was sequenced does not universally represent the considerable genetic and ecological diversity of the species worldwide. The large size of the genome and its high content in repeat-rich sequences of transposable elements was a major difficulty to assemble the Ae. aegypti genome sequence. In the present project, we aim to overcome this difficulty using a novel strategy for genome sequencing and assembly. The ultimate goal is to produce several, fully assembled, well-annotated, new Ae. aegypti reference genomes from epidemiologically relevant populations. The expected outcome is a genome reference panel including a catalog of species-wide genetic variation that will significantly improve genomic resources for Ae. aegypti research and help address a broad range of biological questions related to Ae. aegypti vectorial capacity and dengue virus transmission.



Project status : Closed

Identification of new or unexpected pathogens, including viruses, bacteria, fungi and parasites associated with acute or progressive diseases

Microbial discovery remains a challenging task for which there are a lot of unmet medical and public health needs. Deep sequencing has profoundly modified this field, which can be summarized in two questions : i) which pathogens or association of pathogens are associated with diseases of unknown etiology and ii) among microbes infecting animal (including arthropod) reservoirs, which ones are able to infect large vertebrates, including humans. We are currently addressing these two questions and our current request comes with the willingness for Institut Pasteur to increase its contribution and visibility of this thematic, in particular in relation with hospitals and the Institut Pasteur International network (IPIN).  We expect to identify new microbes associated with human diseases, and this is expected to pave the way for basic research programs focusing on virulence mechanisms and host specificity, and will also lead to phylogenetic and epidemiological studies (frequency of host infection, mode of transmission etc...), as well as the development of improved diagnostic tests for human infections. Our objective is also to contribute to the efforts of Institut Pasteur in the field of infectious diseases, by building a pipeline, from sample to microbial identification, able to manage large cohorts of samples. This project is currently supported by the LABEX IBEID and the CITECH, and critically requires a bioIT support, justifying this application. Partners include different hospitals including Necker-Enfants malades University Hospital regarding patients with progressive disease, different IPIN laboratories, as well as INRA and CIRAD regarding animal/arthropod reservoirs.



Project status : In Progress

IgBlast on Galaxy

We would like to be able to use IgBlast on the Galaxy platform. We are studying B cells in adaptive immune response, and are particularly interested in the antibodies termed as broadly neutralizing antibodies (bNAbs). By definition, these antibodies can neutralize most known HIV-1 strains, and are produced by rare infected individuals several years post-infection. We are currently investigating the bNabs immunoglobulin repertoire by focusing our NGS (454 pyrosequencing) analysis on  immunoglobulin sequences (V-domains) from HIV-infected patients who developed bNAbs. As immunoglobulin sequences result from the combinatorial rearrangement of 3 gene segments : V , (D) and J gene segments, we need a specific tool to analyze these sequences. Indentifying the germline genes which are involved in the rearrangment is an essential step. Two main tools are being widely used to analyze Immunoglobulins: IMGT and IgBlast. IgBlast has several advantages; it is based on BLAST (it is then possible for the user to build his own database), open source, can use protein or nucleotide sequences as input, and most of all, IgBlast is already installed on the Institut Pasteur's cluster as well as the germline genes database. As it would be very convenient for us to use the bic cluster and galaxy platform to run our analyzes, we would be grateful if IgBlast could be implemented in the Pasteur Galaxy Platform. In this regard, we are of course fully disposed to help in any ways. We also believe that it would be very useful to people working on immunoglobulin sequences in the immunology department by building specific pipelines. Thank you very much.



Project status : Closed

IgBlast on Galaxy

We would like to be able to use IgBlast on the Galaxy platform. We are studying B cells in adaptive immune response, and are particularly interested in the antibodies termed as broadly neutralizing antibodies (bNAbs). By definition, these antibodies can neutralize most known HIV-1 strains, and are produced by rare infected individuals several years post-infection. We are currently investigating the bNabs immunoglobulin repertoire by focusing our NGS (454 pyrosequencing) analysis on  immunoglobulin sequences (V-domains) from HIV-infected patients who developed bNAbs. As immunoglobulin sequences result from the combinatorial rearrangement of 3 gene segments : V , (D) and J gene segments, we need a specific tool to analyze these sequences. Indentifying the germline genes which are involved in the rearrangment is an essential step. Two main tools are being widely used to analyze Immunoglobulins: IMGT and IgBlast. IgBlast has several advantages; it is based on BLAST (it is then possible for the user to build his own database), open source, can use protein or nucleotide sequences as input, and most of all, IgBlast is already installed on the Institut Pasteur's cluster as well as the germline genes database. As it would be very convenient for us to use the bic cluster and galaxy platform to run our analyzes, we would be grateful if IgBlast could be implemented in the Pasteur Galaxy Platform. In this regard, we are of course fully disposed to help in any ways. We also believe that it would be very useful to people working on immunoglobulin sequences in the immunology department by building specific pipelines. Thank you very much.



Project status : Closed

Regulation of HIV-1 integration selectivity by chromatin

Integration of the viral reverse-transcribed genome into the genome of infected cells is an essential step of retroviral replication and is performed by a viral-encoded enzyme, named integrase (IN). In the case of HIV-1, IN is a new and efficient anti-viral target. The selectivity of this enzyme for its cellular genomic sites is also a major parameter of HIV replication and is regulated by several cellular parameters. One of them is chromatin, and different levels of this nucleoprotein complex are involved in the regulation of IN selectivity. Using in vitro integration assays, established by our team and collaborators, we have studied this regulation at two levels of chromatin architecture: large poly-nucleosome templates (Botbol et al., 2008; Lesbats et al., 2011; Benleulmi et al., 2015; Naughtin et al., 2015) or nucleosome-induced DNA curvature mimicked by DNA minicircles (Pasi et al., 2016). Our present project is to study IN selectivity into mononucleosomes (MN). These MNs will be used as target substrates of integration and the role of MN structure, histone modifications and IN cofactors will be studied. Results obtained in vitro, will be confronted to structural data obtained by molecular modeling and to integration sites observed in infected cells. This project will benefit from our expertise in integration in chromatin templates and a previous collaboration with the C3BI on the analysis of integration sites (Pasi, M., Mornico, D., S. Volant, S., et al., 2016). This project is funded by the ANRS.



Project status : In Progress

Regulation of HIV-1 integration selectivity by chromatin

Integration of the viral reverse-transcribed genome into the genome of infected cells is an essential step of retroviral replication and is performed by a viral-encoded enzyme, named integrase (IN). In the case of HIV-1, IN is a new and efficient anti-viral target. The selectivity of this enzyme for its cellular genomic sites is also a major parameter of HIV replication and is regulated by several cellular parameters. One of them is chromatin, and different levels of this nucleoprotein complex are involved in the regulation of IN selectivity. Using in vitro integration assays, established by our team and collaborators, we have studied this regulation at two levels of chromatin architecture: large poly-nucleosome templates (Botbol et al., 2008; Lesbats et al., 2011; Benleulmi et al., 2015; Naughtin et al., 2015) or nucleosome-induced DNA curvature mimicked by DNA minicircles (Pasi et al., 2016). Our present project is to study IN selectivity into mononucleosomes (MN). These MNs will be used as target substrates of integration and the role of MN structure, histone modifications and IN cofactors will be studied. Results obtained in vitro, will be confronted to structural data obtained by molecular modeling and to integration sites observed in infected cells. This project will benefit from our expertise in integration in chromatin templates and a previous collaboration with the C3BI on the analysis of integration sites (Pasi, M., Mornico, D., S. Volant, S., et al., 2016). This project is funded by the ANRS.



Project status : In Progress

Utilize mouse models to study infection by HIV-1

We previously showed that humanized immune system (HIS) mice generated in Balb/c Rag2-/-γc-/- SIRPNOD (BRGS) recipients are susceptible to HIV-1 infection (X4 and R5 isolates) and maintain circulating HIV-1 in the plasma, resulting in a dramatic depletion of human CD4+ T cells. We also characterized features of HIV physiopathology in this model. Human thymocyte subsets developing in the thymus of HIS mice appear phenotypically normal, but in the periphery the T cell repertoire is restricted compared with that of human peripheral blood T cells. This negatively impacts on the ability of HIS mice to generate antigen-specific human immune responses when mice are vaccinated with protein antigens or following infection with lymphotropic viruses such as HIV. One likely explanation for these functional deficiencies involves the fact that human T cells are selected intrathymically by mouse MHC molecules and that naïve T cells in peripheral lymphoid organs interact primarily with mouse DC (as human DC development in HIS mice is limited). As a first line of improvement, we recently generated a novel mouse model by crossing our BRGS mice with the HLA-A*02-HHD class I transgenic mice and the HLA-DRB1*15 class II transgenic mice, resulting in BRGS-A2DR2 mice. Following intra-hepatic injection of these mice with MHC-matched CD34+ stem cells we observed increased engraftment, with faster kinetics. Moreover BRGS-A2DR2 HIS mice have an increased T cell development leading to a more equilibrated B/T and CD4/CD8 phenotype. We showed that BRGS-A2DR2 HIS mice were able to sustain replication of HIV R5 virus as the BRGS hosts. Viremia was similar in a first phase and then lower in a second phase in BRGS-A2DR2 compared to BRGS HIS mice, which could be a consequence of a better quality of the immune response. However, the viremia reached a similar plateau in the last phase. We propose to study the impact of the immune res



Project status : Awaiting Publication

Utilize mouse models to study infection by HIV-1

We previously showed that humanized immune system (HIS) mice generated in Balb/c Rag2-/-γc-/- SIRPNOD (BRGS) recipients are susceptible to HIV-1 infection (X4 and R5 isolates) and maintain circulating HIV-1 in the plasma, resulting in a dramatic depletion of human CD4+ T cells. We also characterized features of HIV physiopathology in this model. Human thymocyte subsets developing in the thymus of HIS mice appear phenotypically normal, but in the periphery the T cell repertoire is restricted compared with that of human peripheral blood T cells. This negatively impacts on the ability of HIS mice to generate antigen-specific human immune responses when mice are vaccinated with protein antigens or following infection with lymphotropic viruses such as HIV. One likely explanation for these functional deficiencies involves the fact that human T cells are selected intrathymically by mouse MHC molecules and that naïve T cells in peripheral lymphoid organs interact primarily with mouse DC (as human DC development in HIS mice is limited). As a first line of improvement, we recently generated a novel mouse model by crossing our BRGS mice with the HLA-A*02-HHD class I transgenic mice and the HLA-DRB1*15 class II transgenic mice, resulting in BRGS-A2DR2 mice. Following intra-hepatic injection of these mice with MHC-matched CD34+ stem cells we observed increased engraftment, with faster kinetics. Moreover BRGS-A2DR2 HIS mice have an increased T cell development leading to a more equilibrated B/T and CD4/CD8 phenotype. We showed that BRGS-A2DR2 HIS mice were able to sustain replication of HIV R5 virus as the BRGS hosts. Viremia was similar in a first phase and then lower in a second phase in BRGS-A2DR2 compared to BRGS HIS mice, which could be a consequence of a better quality of the immune response. However, the viremia reached a similar plateau in the last phase. We propose to study the impact of the immune res



Project status : Awaiting Publication

Single cell analysis of HIV-specific CD4+ T cell differentiation



Project status : Awaiting Publication

Single cell analysis of HIV-specific CD4+ T cell differentiation



Project status : Awaiting Publication

Study of the early pathogenesis during Lassa fever in cynomolgus monkeys and its correlation with the outcome

Because of their increasing incidence, dramatic severity, lack of treatment or vaccine, complicated diagnosis, misreading of the pathogenesis, and need for a maximum containment, Viral Hemorrhagic Fevers (VHF) constitute a major public health problem. There is therefore an urgent need to further study VHF to understand the pathogenesis of the severe disease and the host responses involved in their control or in the dramatic damages. Among VHF, Lassa fever (LF) is probably the most worrying one because of its endemicity and the large number of cases. LF is caused by the Old-World arenavirus Lassa virus (LASV). It is endemic to West Africa and is responsible for 300,000 cases and 5,000 to 6,000 deaths each year. We propose here to study the pathogenesis of VHF by using LF in cynomolgus monkeys as a paradigm, with a particular emphasis on the very early events. The viral tropism, pathophysiological mechanisms, and immune responses will be studied during the course of infection, including the incubation period. Powerful approaches will be used to (1) identify early biological markers of infection, to be able to confirm infection and isolate patients; (2) determine the viral tropism and dynamics during the course of infection to understand the natural history of virus into its host. (3) characterize the early pathogenic events that lead to the severe hemorrhagic syndrome to fully understand the pathophysiogenesis of VHF and identify new therapeutic targets. (4) identify the immune responses involved in the control of infection or in the fatal outcome, to reveal the involvement of immunopathological mechanisms and help to design a vaccine approach. This ambitious and unprecedented project will allow to develop therapeutic and prophylactic approaches but also to identify early biological markers of infection and improve the early diagnosis to optimize the management of outbreaks in the field and increase the survival rate in patients.



Project status : In Progress

Study of the early pathogenesis during Lassa fever in cynomolgus monkeys and its correlation with the outcome

Because of their increasing incidence, dramatic severity, lack of treatment or vaccine, complicated diagnosis, misreading of the pathogenesis, and need for a maximum containment, Viral Hemorrhagic Fevers (VHF) constitute a major public health problem. There is therefore an urgent need to further study VHF to understand the pathogenesis of the severe disease and the host responses involved in their control or in the dramatic damages. Among VHF, Lassa fever (LF) is probably the most worrying one because of its endemicity and the large number of cases. LF is caused by the Old-World arenavirus Lassa virus (LASV). It is endemic to West Africa and is responsible for 300,000 cases and 5,000 to 6,000 deaths each year. We propose here to study the pathogenesis of VHF by using LF in cynomolgus monkeys as a paradigm, with a particular emphasis on the very early events. The viral tropism, pathophysiological mechanisms, and immune responses will be studied during the course of infection, including the incubation period. Powerful approaches will be used to (1) identify early biological markers of infection, to be able to confirm infection and isolate patients; (2) determine the viral tropism and dynamics during the course of infection to understand the natural history of virus into its host. (3) characterize the early pathogenic events that lead to the severe hemorrhagic syndrome to fully understand the pathophysiogenesis of VHF and identify new therapeutic targets. (4) identify the immune responses involved in the control of infection or in the fatal outcome, to reveal the involvement of immunopathological mechanisms and help to design a vaccine approach. This ambitious and unprecedented project will allow to develop therapeutic and prophylactic approaches but also to identify early biological markers of infection and improve the early diagnosis to optimize the management of outbreaks in the field and increase the survival rate in patients.



Project status : In Progress

The resurgence of a neglected disease, Yellow fever: from jungle to urban environments

Yellow fever virus (YFV), a Flavivirus transmitted by mosquitoes causes a severe hemorrhagic fever in humans. Despite the availability of a safe and effective vaccine (17D), YFV is still a public health problem in tropical Africa and South America. In the Americas, the massive campaign of mosquito control during the first half of the 20th century led to the eradication of Aedes aegypti from most American countries, and as a consequence, urban outbreaks of YF were no longer observed. However, the relaxation of vector control led to the reinfestation of urban areas by Ae. aegypti and the subsequent establishment of the Asian tiger mosquito Aedes albopictus. In Brazil, while human cases are sporadically detected in the Amazonian basin where sylvatic YFV strains circulate between non-human primates and arboreal canopy-dwelling mosquitoes (Haemagogus sp.), they are increasingly reported outside the jungle moving towards the Atlantic coast, the most populated area. In the absence of routine immunization programs, YF may come back in the American towns as it was in the past. The causes leading to the current YF resurgence are multifactorial. From a mosquito vector viewpoint, changes in vector densities, distribution, vector competence or vector as a site of selection for epidemic YFV strains, can be regarded as critical factors. Our project aims to address the contribution of the invasive mosquito Ae. albopictus as a missing link to allow a selvatic YF strain (1D) to become adapted for a transmission in urban areas by the human-biting mosquito, Ae. aegypti. It will be done through three specific objectives: (i) identify Ae. albopictus-adaptive mutations after serial cycling of the selvatic YFV-1D on Brazilian Ae. albopictus mosquitoes, (ii) evaluate their potential to be transmitted to a vertebrate host, and (iii) deepen the transmission of the experimentally selected viruses by field-collected mosquito populations.



Project status : Closed

The resurgence of a neglected disease, Yellow fever: from jungle to urban environments

Yellow fever virus (YFV), a Flavivirus transmitted by mosquitoes causes a severe hemorrhagic fever in humans. Despite the availability of a safe and effective vaccine (17D), YFV is still a public health problem in tropical Africa and South America. In the Americas, the massive campaign of mosquito control during the first half of the 20th century led to the eradication of Aedes aegypti from most American countries, and as a consequence, urban outbreaks of YF were no longer observed. However, the relaxation of vector control led to the reinfestation of urban areas by Ae. aegypti and the subsequent establishment of the Asian tiger mosquito Aedes albopictus. In Brazil, while human cases are sporadically detected in the Amazonian basin where sylvatic YFV strains circulate between non-human primates and arboreal canopy-dwelling mosquitoes (Haemagogus sp.), they are increasingly reported outside the jungle moving towards the Atlantic coast, the most populated area. In the absence of routine immunization programs, YF may come back in the American towns as it was in the past. The causes leading to the current YF resurgence are multifactorial. From a mosquito vector viewpoint, changes in vector densities, distribution, vector competence or vector as a site of selection for epidemic YFV strains, can be regarded as critical factors. Our project aims to address the contribution of the invasive mosquito Ae. albopictus as a missing link to allow a selvatic YF strain (1D) to become adapted for a transmission in urban areas by the human-biting mosquito, Ae. aegypti. It will be done through three specific objectives: (i) identify Ae. albopictus-adaptive mutations after serial cycling of the selvatic YFV-1D on Brazilian Ae. albopictus mosquitoes, (ii) evaluate their potential to be transmitted to a vertebrate host, and (iii) deepen the transmission of the experimentally selected viruses by field-collected mosquito populations.



Project status : Closed