L’infection zoonotique par les virus foamy simiens : une réponse anticorps puissante

International audienceL’homme n’est pas un hôte naturel des virus foamy (VF), mais il peut être infecté par des VF simiens (VFS), principalement suite à une morsure par un singe infecté [...

Les rétrovirus foamy zoonotiques : une première étude médicale chez les personnes infectées

International audienceLes émergences infectieuses zoonotiques sont un enjeu majeur de santé publique [1-3] ( ➜ ). Deux familles de rétrovirus ont émergé dans la population humaine depuis un réservoir simien: les virus de l’immunodéficience humaine (VIH) et les virus humains T lymphotropes (human T lymphotropic virus, HTLV). La pandémie du VIH est une des plus récentes et des plus importantes de l’histoire

Traitement précoce des nourrissons vivant avec le VIH-1

International audienceHIV-1 infection has several distinctive features in children compared to adults, especially (i) the occurrence of the primary infection during a period of high vulnerability because of the immaturity of the immune system, which partly explains that around 15% of children experience a rapidly unfavourable clinical course with death before 3-4 years-of-age (in the absence of antiretroviral therapy (ART)), and (ii) the capacity of immune restoration under ART is higher in children than in adults, which is probably partly explained by an improved thymic activity. Thus, it has recently been suggested that early ART initiation in HIV-1-infected children could protect the immune system from HIV-induced damages during the critical period of immunological immaturity. This “protective” effect could have a long-term impact, partly because specific immune responses against HIV could be developed more efficiently in case of later re-exposure to HIV viremia. Finally, early ART initiation could also have virological benefits, because of the drastic reduction of the size of the viral reservoir.L'infection à VIH-1 présente deux spécificités majeures chez l'enfant par rapport à l'adulte. La première est la présence d'une forme très rapide de la maladie chez environ 15% des nourrissons qui connaissent une évolution précoce vers la forme SIDA avec décès avant l'âge de 3-4 ans (en l'absence de traitement antiviral). Cette évolution s'explique par l'immaturité du système immunitaire des nourrissons, qui rend leur organisme particulièrement vulnérable aux dommages causés par le virus. La seconde spécificité est que, sous traitement antiviral, la restauration des défenses immunitaires des enfants est bien meilleure que celle observée chez les adultes. L'instauration systématique d'une multithérapie antirétrovirale dès les premiers mois de vie a un bénéfice indiscutable en terme de mortalité néonatale. Elle pourrait également apporter un bénéfice à long terme, en limitant rapidement la constitution du réservoir viral et en protégeant le système immunitaire des nourrissons des dommages viro-induits

A new sensitive indicator cell line reveals cross-transactivation of the viral LTR by gorilla and chimpanzee simian foamy viruses

International audienceThe majority of currently identified simian foamy virus (SFV)-infected Cameroonian and Gabonese individuals harbor SFV from the gorilla lineage. We constructed an indicator cell line for the quantification of gorilla SFVs, in which the U3 sequence of a gorilla SFV directs the expression of the β-galactosidase protein. The gorilla foamy virus activated β-galactosidase (GFAB) cells efficiently quantified two zoonotic primary gorilla isolates and SFVs from three chimpanzee subspecies. Primary gorilla SFVs replicated more slowly and at lower levels than primary chimpanzee SFVs. Analysis of previously described motifs of Tas proteins and U3 LTRs involved in viral gene synthesis revealed conservation of such motifs in Tas proteins from gorilla and chimpanzee SFVs, but little sequence homology in the LTR regions previously shown to interact with viral and cellular factors

A new sensitive indicator cell line reveals cross-transactivation of the viral LTR by gorilla and chimpanzee simian foamy viruses

International audienceThe majority of currently identified simian foamy virus (SFV)-infected Cameroonian and Gabonese individuals harbor SFV from the gorilla lineage. We constructed an indicator cell line for the quantification of gorilla SFVs, in which the U3 sequence of a gorilla SFV directs the expression of the β-galactosidase protein. The gorilla foamy virus activated β-galactosidase (GFAB) cells efficiently quantified two zoonotic primary gorilla isolates and SFVs from three chimpanzee subspecies. Primary gorilla SFVs replicated more slowly and at lower levels than primary chimpanzee SFVs. Analysis of previously described motifs of Tas proteins and U3 LTRs involved in viral gene synthesis revealed conservation of such motifs in Tas proteins from gorilla and chimpanzee SFVs, but little sequence homology in the LTR regions previously shown to interact with viral and cellular factors

Latency, tropism and genetic variation of Simian Foamy Virus in blood and saliva from infected Humans

International audienceSimian foamy viruses (SFV) are widespread retroviruses among non-human primates (NHP). SFV actively replicate in the oral cavity of NHP and can be transmitted to humans through NHP bites, in whom they establish a persistent infection. We aimed to study three major properties of these zoonotic retroviruses: replicative status, tropism and variability. In 14 hunters from Cameroon previously shown to be infected with a gorilla SFV strain, viral DNA could be detected by quantitative polymerase chain reaction in most samples of peripheral blood mononuclear cells (PBMCs) and saliva. The SFV DNA levels were 7.1±6.0 SFV DNA copies/105 cells in PBMCs and 2.4±4.3 SFV DNA copies/105 cells in saliva. In contrast, no SFV RNA was detected by qRT-PCR in either PBMCs or saliva. PBMCs populations (T4, T8, B, NK lymphocytes and monocytes) were sorted with magnetic beads before quantification of SFV DNA. Our preliminary results showed the presence of SFV DNA in all PBMCs populations at different levels. We finally assessed the viral diversity in vivo. Although intra-individual SFV genetic variation was low (<0,5%) we detected some viral diversity in 3 out of 9 individuals. In one subject, genetic variation might be associated with coinfection with 2 SFV strains, while in the two other subjects, variations seemed to derive from APOBEC3 editing with a high rate of G-to-A substitutions. Our study demonstrates that SFV infection is mostly latent in PBMCs and in saliva. Such a scenario may explain the putative lack of secondary human-to-human transmissions of SFV

In vivo cellular tropism of gorilla simian foamy virus in blood of infected humans.

International audienceSimian foamy viruses (SFV) are retroviruses that are widespread among nonhuman primates. SFV can be transmitted to humans, giving rise to a persistent infection. Only a few data are available concerning the distribution of SFV in human blood cells. Here we purified blood mononuclear cell subsets from 11 individuals infected with a Gorilla gorilla SFV strain and quantified SFV DNA levels by quantitative PCR. SFV DNA was detected in the majority of the CD8(+), CD4(+), and CD19(+) lymphocyte samples and rarely in CD14(+) monocyte and CD56(+) NK lymphocyte samples. The median (interquartile range [IQR]) SFV DNA counts were 16.0 (11.0 to 49.8), 11.3 (5.9 to 28.3), and 17.2 (2.0 to 25.2) copies/10(5) cells in CD8(+) T lymphocytes, CD4(+) T lymphocytes, and CD19(+) B lymphocytes, respectively. In the CD4 compartment, SFV DNA was detected in both memory and naive CD4(+) T lymphocytes. SFV DNA levels in CD4(+) T cells were positively correlated with the duration of the infection. Our study shows with a quantitative method that CD8(+), CD4(+), and B lymphocytes are major cellular targets of SFV in the blood of infected humans.Investigation of SFV infections in humans is important due to the origin of human immunodeficiency viruses (HIV) and human T cell lymphotropic viruses (HTLV) from cross-species transmission of their simian counterparts to humans. Surprisingly little is known about many aspects of the biology of SFV in infected humans, including quantitative data concerning the cellular targets of SFV in vivo. Here we show that the distribution of SFV DNA among the different leukocyte populations is not homogeneous and that viral load in CD4(+) T lymphocytes is correlated with the duration of infection. These new data will help in understanding the biology of retroviral infections in humans and can be useful in the growing field of SFV-based gene therapy

Inhibitors of the Interferon Response Increase the Replication of Gorilla Simian Foamy Viruses

International audienceSimian foamy viruses (SFVs) are complex retroviruses widespread throughout nonhuman primates. SFVs can also be transmitted to humans, mostly through bites. We previously observed that the primary zoonotic gorilla SFV strains much more slowly than laboratory-adapted chimpanzee strains. Here, we tested the hypothesis that SFV growth is limited by interferon (IFN)-induced restriction factors using inhibitors of cellular signaling pathways involved in type I IFN induction or action. Inhibitors of JAK1/2 (Ruxolitinib) and TBK-1 (BMX795) led to a 2 to > 20-fold higher percentage of infected BHK-1 and HT1080 cells. However, replication of the laboratory-adapted prototype foamy virus was not sensitive to these molecules, and IKK2 inhibitors had no effect on any of the SFV strains. In conclusion, the addition of small molecules that inhibit type I IFN response to the culture medium can be used as a simple and efficient method to enhance the replication of zoonotic gorilla SFV

La réponse immunitaire cellulaire contre la protéine gag du VIH-1

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Plasma antibodies from humans infected with zoonotic simian foamy virus do not inhibit cell-to-cell transmission of the virus despite binding to the surface of infected cells

International audienceZoonotic simian foamy viruses (SFV) establish lifelong infection in their human hosts. Despite repeated transmission of SFV from nonhuman primates to humans, neither transmission between human hosts nor severe clinical manifestations have been reported. We aim to study the immune responses elicited by chronic infection with this retrovirus and previously reported that SFV-infected individuals generate potent neutralizing antibodies that block cell infection by viral particles. Here, we assessed whether human plasma antibodies block SFV cell-to-cell transmission and present the first description of cell-to-cell spreading of zoonotic gorilla SFV. We set-up a microtitration assay to quantify the ability of plasma samples from 20 Central African individuals infected with gorilla SFV and 9 uninfected controls to block cell-associated transmission of zoonotic gorilla SFV strains. We used flow-based cell cytometry and fluorescence microscopy to study envelope protein (Env) localization and the capacity of plasma antibodies to bind to infected cells. We visualized the cell-to-cell spread of SFV by real-time live imaging of a GFP-expressing prototype foamy virus (CI-PFV) strain. None of the samples neutralized cell-associated SFV infection, despite the inhibition of cell-free virus. We detected gorilla SFV Env in the perinuclear region, cytoplasmic vesicles and at the cell surface. We found that plasma antibodies bind to Env located at the surface of cells infected with primary gorilla SFV strains. Extracellular labeling of SFV proteins by human plasma samples showed patchy staining at the base of the cell and dense continuous staining at the cell apex, as well as staining in the intercellular connections that formed when previously connected cells separated from each other. In conclusion, SFV-specific antibodies from infected humans do not block cell-to-cell transmission, at least in vitro , despite their capacity to bind to the surface of infected cells