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1.
Retrovirology ; 16(1): 39, 2019 12 16.
Artículo en Inglés | MEDLINE | ID: mdl-31842895

RESUMEN

Human T cell leukemia virus (HTLV-1) is an oncoretrovirus that infects at least 10 million people worldwide. HTLV-1 exhibits a remarkable genetic stability, however, viral strains have been classified in several genotypes and subgroups, which often mirror the geographic origin of the viral strain. The Cosmopolitan genotype HTLV-1a, can be subdivided into geographically related subgroups, e.g. Transcontinental (a-TC), Japanese (a-Jpn), West-African (a-WA), North-African (a-NA), and Senegalese (a-Sen). Within each subgroup, the genetic diversity is low. Genotype HTLV-1b is found in Central Africa; it is the major genotype in Gabon, Cameroon and Democratic Republic of Congo. While strains from the HTLV-1d genotype represent only a few percent of the strains present in Central African countries, genotypes -e, -f, and -g have been only reported sporadically in particular in Cameroon Gabon, and Central African Republic. HTLV-1c genotype, which is found exclusively in Australo-Melanesia, is the most divergent genotype. This reflects an ancient speciation, with a long period of isolation of the infected populations in the different islands of this region (Australia, Papua New Guinea, Solomon Islands and Vanuatu archipelago). Until now, no viral genotype or subgroup is associated with a specific HTLV-1-associated disease. HTLV-1 originates from a simian reservoir (STLV-1); it derives from interspecies zoonotic transmission from non-human primates to humans (ancient or recent). In this review, we describe the genetic diversity of HTLV-1, and analyze the molecular mechanisms that are at play in HTLV-1 evolution. Similar to other retroviruses, HTLV-1 evolves either through accumulation of point mutations or recombination. Molecular studies point to a fairly low evolution rate of HTLV-1 (between 5.6E-7 and 1.5E-6 substitutions/site/year), supposedly because the virus persists within the host via clonal expansion (instead of new infectious cycles that use reverse transcriptase).


Asunto(s)
Evolución Molecular , Variación Genética , Genotipo , Infecciones por HTLV-I/epidemiología , Virus Linfotrópico T Tipo 1 Humano/genética , África/epidemiología , Animales , Infecciones por HTLV-I/virología , Humanos , Epidemiología Molecular , Mutación , Filogenia , Primates/virología , ARN Viral/genética , Virus Linfotrópico T Tipo 1 de los Simios/genética
2.
Nature ; 498(7454): 371-5, 2013 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-23708969

RESUMEN

Neutrophil recruitment from blood to extravascular sites of sterile or infectious tissue damage is a hallmark of early innate immune responses, and the molecular events leading to cell exit from the bloodstream have been well defined. Once outside the vessel, individual neutrophils often show extremely coordinated chemotaxis and cluster formation reminiscent of the swarming behaviour of insects. The molecular players that direct this response at the single-cell and population levels within the complexity of an inflamed tissue are unknown. Using two-photon intravital microscopy in mouse models of sterile injury and infection, we show a critical role for intercellular signal relay among neutrophils mediated by the lipid leukotriene B4, which acutely amplifies local cell death signals to enhance the radius of highly directed interstitial neutrophil recruitment. Integrin receptors are dispensable for long-distance migration, but have a previously unappreciated role in maintaining dense cellular clusters when congregating neutrophils rearrange the collagenous fibre network of the dermis to form a collagen-free zone at the wound centre. In this newly formed environment, integrins, in concert with neutrophil-derived leukotriene B4 and other chemoattractants, promote local neutrophil interaction while forming a tight wound seal. This wound seal has borders that cease to grow in kinetic concert with late recruitment of monocytes and macrophages at the edge of the displaced collagen fibres. Together, these data provide an initial molecular map of the factors that contribute to neutrophil swarming in the extravascular space of a damaged tissue. They reveal how local events are propagated over large-range distances, and how auto-signalling produces coordinated, self-organized neutrophil-swarming behaviour that isolates the wound or infectious site from surrounding viable tissue.


Asunto(s)
Factores Quimiotácticos/metabolismo , Quimiotaxis de Leucocito , Integrinas/metabolismo , Leucotrieno B4/metabolismo , Infiltración Neutrófila , Neutrófilos/citología , Cicatrización de Heridas/fisiología , Animales , Muerte Celular , Factores Quimiotácticos/inmunología , Quimiotaxis de Leucocito/inmunología , Colágeno/metabolismo , Femenino , Inmunidad Innata , Leucotrieno B4/inmunología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Macrófagos/citología , Macrófagos/microbiología , Macrófagos/patología , Masculino , Ratones , Neutrófilos/fisiología , Pseudomonas aeruginosa/patogenicidad , Receptores Acoplados a Proteínas G/metabolismo , Piel/citología , Piel/lesiones , Piel/patología
3.
Artículo en Inglés | MEDLINE | ID: mdl-28807907

RESUMEN

De novo pyrimidine biosynthesis is a key metabolic pathway involved in multiple biosynthetic processes. Here, we identified an original series of 3-(1H-indol-3-yl)-2,3-dihydro-4H-furo[3,2-c]chromen-4-one derivatives as a new class of pyrimidine biosynthesis inhibitors formed by two edge-fused polycyclic moieties. We show that identified compounds exhibit broad-spectrum antiviral activity and immunostimulatory properties, in line with recent reports linking de novo pyrimidine biosynthesis with innate defense mechanisms against viruses. Most importantly, we establish that pyrimidine deprivation can amplify the production of both type I and type III interferons by cells stimulated with retinoic acid-inducible gene 1 (RIG-I) ligands. Altogether, our results further expand the current panel of pyrimidine biosynthesis inhibitors and illustrate how the production of antiviral interferons is tightly coupled to this metabolic pathway. Functional and structural similarities between this new chemical series and dicoumarol, which was reported before to inhibit pyrimidine biosynthesis at the dihydroorotate dehydrogenase (DHODH) step, are discussed.


Asunto(s)
Antivirales/farmacología , Virus Chikungunya/inmunología , Cromonas/farmacología , Inhibidores Enzimáticos/farmacología , Indoles/farmacología , Interferón Tipo I/biosíntesis , Interferones/biosíntesis , Virus del Sarampión/inmunología , Pirimidinas/biosíntesis , Antivirales/química , Línea Celular , Cromonas/química , Dicumarol/farmacología , Dihidroorotato Deshidrogenasa , Inhibidores Enzimáticos/química , Células HEK293 , Humanos , Inmunidad Innata/inmunología , Indoles/química , Interferón Tipo I/inmunología , Interferones/inmunología , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Relación Estructura-Actividad , Interferón lambda
4.
J Virol ; 90(16): 7303-7312, 2016 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-27252538

RESUMEN

UNLABELLED: Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of a slowly progressive neurodegenerative disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This disease develops upon infiltration of HTLV-1-infected lymphocytes into the central nervous system, mostly the thoracic spinal cord. The central nervous system is normally protected by a physiological structure called the blood-brain barrier (BBB), which consists primarily of a continuous endothelium with tight junctions. In this study, we investigated the role of activated leukocyte cell adhesion molecule (ALCAM/CD166), a member of the immunoglobulin superfamily, in the crossing of the BBB by HTLV-1-infected lymphocytes. We demonstrated that ALCAM is overexpressed on the surface of HTLV-1-infected lymphocytes, both in chronically infected cell lines and in primary infected CD4(+) T lymphocytes. ALCAM overexpression results from the activation of the canonical NF-κB pathway by the viral transactivator Tax. In contrast, staining of spinal cord sections of HAM/TSP patients showed that ALCAM expression is not altered on the BBB endothelium in the context of HTLV-1 infection. ALCAM blockade or downregulation of ALCAM levels significantly reduced the migration of HTLV-1-infected lymphocytes across a monolayer of human BBB endothelial cells. This study suggests a potential role for ALCAM in HAM/TSP pathogenesis. IMPORTANCE: Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of a slowly progressive neurodegenerative disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This disease is the consequence of the infiltration of HTLV-1-infected lymphocytes into the central nervous system (CNS), mostly the thoracic spinal cord. The CNS is normally protected by a physiological structure called the blood-brain barrier (BBB), which consists primarily of a continuous endothelium with tight junctions. The mechanism of migration of lymphocytes into the CNS is unclear. Here, we show that the viral transactivator Tax increases activated leukocyte cell adhesion molecule (ALCAM/CD166) expression. This molecule facilitates the migration of lymphocytes across the BBB endothelium. Targeting this molecule could be of interest in preventing or reducing the development of HAM/TSP.


Asunto(s)
Antígenos CD/metabolismo , Barrera Hematoencefálica , Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD4-Positivos/virología , Moléculas de Adhesión Celular Neuronal/metabolismo , Movimiento Celular , Proteínas Fetales/metabolismo , Interacciones Huésped-Patógeno , Virus Linfotrópico T Tipo 1 Humano/fisiología , Linfocitos T CD4-Positivos/química , Línea Celular , Células Endoteliales/química , Productos del Gen tax/metabolismo , Humanos , FN-kappa B/metabolismo
5.
Virologie (Montrouge) ; 21(1): 11-18, 2017 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31967563

RESUMEN

HTLV-1 (Human T-cell Lymphotropic Virus Type 1) is a human retrovirus that infects around 10 million people worldwide. It can be transmitted by sexual contact, transfusion of contaminated blood, and from infected mother-to-child during prolonged breastfeeding. The latter involves viral crossing of the digestive tract. HTLV-1 is the etiological agent of both a lymphoproliferative malignancy, Adult T-cell leukemia/lymphoma, and a chronic inflammatory neuromyelopathy, the Tropical Spastic Paraparesis/HTLV-1 Associated Myelopathy (TSP/HAM). TSP/HAM is characterized by HTLV-1-infected lymphocyte infiltration in the central nervous system; these cells cross the blood-brain barrier, an anatomical barrier that normally isolates and protects the central nervous system from blood. In this context, the present review focuses on latest findings and opinions on the interactions of HTLV-1 with the intestinal barrier, as involved in mother-to-child viral transmission, and with the blood-brain barrier, as involved in TSP/HAM pathogenesis.

6.
J Virol ; 89(24): 12480-91, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26446599

RESUMEN

UNLABELLED: Simian foamy virus (SFV) is a ubiquitous retrovirus in nonhuman primates (NHPs) that can be transmitted to humans, mostly through severe bites. In the past few years, our laboratory has identified more than 50 hunters from central Africa infected with zoonotic SFVs. Analysis of the complete sequences of five SFVs obtained from these individuals revealed that env was the most variable gene. Furthermore, recombinant SFV strains, some of which involve sequences in the env gene, were recently identified. Here, we investigated the variability of the env genes of zoonotic SFV strains and searched for possible recombinants. We sequenced the complete env gene or its surface glycoprotein region (SU) from DNA amplified from the blood of (i) a series of 40 individuals from Cameroon or Gabon infected with a gorilla or chimpanzee foamy virus (FV) strain and (ii) 1 gorilla and 3 infected chimpanzees living in the same areas as these hunters. Phylogenetic analyses revealed the existence of two env variants among both the gorilla and chimpanzee FV strains that were present in zoonotic and NHP strains. These variants differ greatly (>30% variability) in a 753-bp-long region located in the receptor-binding domain of SU, whereas the rest of the gene is very conserved. Although the organizations of the Env protein sequences are similar, the potential glycosylation patterns differ between variants. Analysis of recombination suggests that the variants emerged through recombination between different strains, although all parental strains could not be identified. IMPORTANCE: SFV infection in humans is a great example of a zoonotic retroviral infection that has not spread among human populations, in contrast to human immunodeficiency viruses (HIVs) and human T-lymphotropic viruses (HTLVs). Recombination was a major mechanism leading to the emergence of HIV. Here, we show that two SFV molecular envelope gene variants circulate among ape populations in Central Africa and that both can be transmitted to humans. These variants differ greatly in the SU region that corresponds to the part of the Env protein in contact with the environment. These variants may have emerged through recombination between SFV strains infecting different NHP species.


Asunto(s)
Productos del Gen env/genética , Filogenia , Recombinación Genética , Infecciones por Retroviridae/genética , Virus Espumoso de los Simios/genética , Animales , Enfermedades del Simio Antropoideo/epidemiología , Enfermedades del Simio Antropoideo/genética , Enfermedades del Simio Antropoideo/virología , Camerún , Gabón , Gorilla gorilla , Humanos , Pan troglodytes , Infecciones por Retroviridae/epidemiología , Infecciones por Retroviridae/veterinaria
7.
PLoS Pathog ; 10(2): e1003917, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24586148

RESUMEN

Efficient HTLV-1 viral transmission occurs through cell-to-cell contacts. The Tax viral transcriptional activator protein facilitates this process. Using a comparative transcriptomic analysis, we recently identified a series of genes up-regulated in HTLV-1 Tax expressing T-lymphocytes. We focused our attention towards genes that are important for cytoskeleton dynamic and thus may possibly modulate cell-to-cell contacts. We first demonstrate that Gem, a member of the small GTP-binding proteins within the Ras superfamily, is expressed both at the RNA and protein levels in Tax-expressing cells and in HTLV-1-infected cell lines. Using a series of ChIP assays, we show that Tax recruits CREB and CREB Binding Protein (CBP) onto a c-AMP Responsive Element (CRE) present in the gem promoter. This CRE sequence is required to drive Tax-activated gem transcription. Since Gem is involved in cytoskeleton remodeling, we investigated its role in infected cells motility. We show that Gem co-localizes with F-actin and is involved both in T-cell spontaneous cell migration as well as chemotaxis in the presence of SDF-1/CXCL12. Importantly, gem knock-down in HTLV-1-infected cells decreases cell migration and conjugate formation. Finally, we demonstrate that Gem plays an important role in cell-to-cell viral transmission.


Asunto(s)
Citoesqueleto/metabolismo , Virus Linfotrópico T Tipo 1 Humano , Proteínas de Unión al GTP Monoméricas/metabolismo , Linfocitos T/metabolismo , Linfocitos T/virología , Línea Celular , Quimiotaxis de Leucocito/fisiología , Inmunoprecipitación de Cromatina , Técnica del Anticuerpo Fluorescente , Regulación Viral de la Expresión Génica/fisiología , Productos del Gen tax/metabolismo , Immunoblotting , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T/patología , Activación Transcripcional/fisiología , Transducción Genética
8.
J Biol Chem ; 289(32): 22284-305, 2014 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-24939845

RESUMEN

Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. The HTLV-1 transactivator protein Tax controls many critical cellular pathways, including host cell DNA damage response mechanisms, cell cycle progression, and apoptosis. Extracellular vesicles called exosomes play critical roles during pathogenic viral infections as delivery vehicles for host and viral components, including proteins, mRNA, and microRNA. We hypothesized that exosomes derived from HTLV-1-infected cells contain unique host and viral proteins that may contribute to HTLV-1-induced pathogenesis. We found exosomes derived from infected cells to contain Tax protein and proinflammatory mediators as well as viral mRNA transcripts, including Tax, HBZ, and Env. Furthermore, we observed that exosomes released from HTLV-1-infected Tax-expressing cells contributed to enhanced survival of exosome-recipient cells when treated with Fas antibody. This survival was cFLIP-dependent, with Tax showing induction of NF-κB in exosome-recipient cells. Finally, IL-2-dependent CTLL-2 cells that received Tax-containing exosomes were protected from apoptosis through activation of AKT. Similar experiments with primary cultures showed protection and survival of peripheral blood mononuclear cells even in the absence of phytohemagglutinin/IL-2. Surviving cells contained more phosphorylated Rb, consistent with the role of Tax in regulation of the cell cycle. Collectively, these results suggest that exosomes may play an important role in extracellular delivery of functional HTLV-1 proteins and mRNA to recipient cells.


Asunto(s)
Productos del Gen tax/metabolismo , Virus Linfotrópico T Tipo 1 Humano/fisiología , Virus Linfotrópico T Tipo 1 Humano/patogenicidad , Línea Celular , Supervivencia Celular , Células Dendríticas/inmunología , Células Dendríticas/fisiología , Células Dendríticas/virología , Exosomas/metabolismo , Exosomas/virología , Productos del Gen tax/inmunología , Infecciones por HTLV-I/etiología , Infecciones por HTLV-I/fisiopatología , Infecciones por HTLV-I/virología , Interacciones Huésped-Patógeno , Virus Linfotrópico T Tipo 1 Humano/inmunología , Humanos , Virulencia , Receptor fas/antagonistas & inhibidores
9.
J Virol ; 88(17): 9782-8, 2014 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-24942582

RESUMEN

UNLABELLED: Although recombination is a major source of genetic variability in retroviruses, no recombinant strain had been observed for human T-lymphotropic virus type 1 (HTLV-1), the first isolated human-pathogenic retrovirus. Different genotypes exist for HTLV-1: Genotypes b and d to g are restricted to central Africa, while genotype c is only endemic in Australo-Melanesia. In contrast, the cosmopolitan genotype a is widely distributed. We applied a combination of phylogenetics and recombination analysis approaches to a set of new HTLV-1 sequences, which we collected from 19 countries throughout Africa, the continent where the virus has the largest endemic presence. This led us to demonstrate the presence of recombinants in HTLV-1. Indeed, the HTLV-1 strains currently present in North Africa have originated from a recombinant event between strains from Senegal and West Africa. This recombination is estimated to have occurred around 4,000 years ago. This recombination seems to have been generated during reverse transcription. In conclusion, we demonstrate that, albeit rare, recombination can occur in HTLV-1 and may play a role in the evolution of this retrovirus. IMPORTANCE: A number of HTLV-1 subtypes have been described in different populations, but none of the genetic differences between these subtypes have been ascribed to recombination events. Here we report an HTLV-1 recombinant virus among infected individuals in North Africa. This demonstrates that, contrary to what was thought, recombination can occur and could play a role in the evolution of HTLV-1.


Asunto(s)
Evolución Molecular , Infecciones por HTLV-I/virología , Virus Linfotrópico T Tipo 1 Humano/clasificación , Virus Linfotrópico T Tipo 1 Humano/genética , Recombinación Genética , Adolescente , Adulto , África del Norte/epidemiología , Anciano , Análisis por Conglomerados , Femenino , Infecciones por HTLV-I/epidemiología , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Epidemiología Molecular , Filogenia , Adulto Joven
10.
Blood ; 121(9): 1644-50, 2013 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-23233663

RESUMEN

Neutrophils express a variety of collagen receptors at their surface, yet their functional significance remains unclear. Although integrins are essential for neutrophil adhesion and migration on 2-dimensional (2D) surfaces, neutrophils can compensate for the absence of integrins in 3-dimensional (3D) lattices. In contrast, we demonstrate that the inhibition of the tyrosine-kinase collagen receptor discoidin domain receptor 2 (DDR2) has no impact on human primary neutrophil migration on 2D surfaces but is an important regulator of neutrophil chemotaxis in 3D collagen matrices. In this context, we show that DDR2 activation specifically regulates the directional migration of neutrophils in chemoattractant gradients. We further demonstrate that DDR2 regulates directionality through its ability to increase secretion of metalloproteinases and local generation of collagen-derived chemotactic peptide gradients. Our findings highlight the importance of collagen-derived extracellular signaling during neutrophil chemotaxis in 3D matrices.


Asunto(s)
Quimiotaxis de Leucocito , Neutrófilos/fisiología , Proteínas Tirosina Quinasas Receptoras/fisiología , Receptores Mitogénicos/fisiología , Técnicas de Cultivo de Tejidos , Ensayos de Migración de Leucocitos/métodos , Polaridad Celular/efectos de los fármacos , Células Cultivadas , Quimiotaxis de Leucocito/efectos de los fármacos , Quimiotaxis de Leucocito/fisiología , Colágeno/química , Colágeno/farmacología , Dipéptidos/farmacología , Receptores con Dominio Discoidina , Matriz Extracelular/química , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Cultivo Primario de Células , Inhibidores de Proteasas/farmacología , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores Mitogénicos/metabolismo , Técnicas de Cultivo de Tejidos/métodos , Andamios del Tejido/química
12.
Front Immunol ; 14: 1043600, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36817417

RESUMEN

The African continent is considered the largest high endemic area for the oncogenic retrovirus HTLV-1 with an estimated two to five million infected individuals. However, data on epidemiological aspects, in particular prevalence, risk factors and geographical distribution, are still very limited for many regions: on the one hand, few large-scale and representative studies have been performed and, on the other hand, many studies do not include confirmatory tests, resulting in indeterminate serological results, and a likely overestimation of HTLV-1 seroprevalence. For this review, we included the most robust studies published since 1984 on the prevalence of HTLV-1 and the two major diseases associated with this infection in people living in Africa and the Indian Ocean islands: adult T-cell leukemia (ATL) and tropical spastic paraparesis or HTLV-1-associated myelopathy (HAM/TSP). We also considered most of the book chapters and abstracts published at the 20 international conferences on HTLV and related viruses held since 1985, as well as the results of recent meta-analyses regarding the status of HTLV-1 in West and sub-Saharan Africa. Based on this bibliography, it appears that HTLV-1 distribution is very heterogeneous in Africa: The highest prevalences of HTLV-1 are reported in western, central and southern Africa, while eastern and northern Africa show lower prevalences. In highly endemic areas, the HTLV-1 prevalence in the adult population ranges from 0.3 to 3%, increases with age, and is highest among women. In rural areas of Gabon and the Democratic Republic of the Congo (DRC), HTLV-1 prevalence can reach up to 10-25% in elder women. HTLV-1-associated diseases in African patients have rarely been reported in situ on hospital wards, by local physicians. With the exception of the Republic of South Africa, DRC and Senegal, most reports on ATL and HAM/TSP in African patients have been published by European and American clinicians and involve immigrants or medical returnees to Europe (France and the UK) and the United States. There is clearly a huge underreporting of these diseases on the African continent. The genetic diversity of HTLV-1 is greatest in Africa, where six distinct genotypes (a, b, d, e, f, g) have been identified. The most frequent genotype in central Africa is genotype b. The other genotypes found in central Africa (d, e, f and g) are very rare. The vast majority of HTLV-1 strains from West and North Africa belong to genotype a, the so-called 'Cosmopolitan' genotype. These strains form five clades roughly reflecting the geographic origin of the infected individuals. We have recently shown that some of these clades are the result of recombination between a-WA and a-NA strains. Almost all sequences from southern Africa belong to Transcontinental a-genotype subgroup.


Asunto(s)
Infecciones por HTLV-I , Virus Linfotrópico T Tipo 1 Humano , Paraparesia Espástica Tropical , Adulto , Humanos , Femenino , Anciano , Estudios Seroepidemiológicos , Sistemas de Distribución en Hospital , Variación Genética , Sudáfrica
13.
Blood ; 116(19): 3802-8, 2010 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-20587783

RESUMEN

Approximately 3% of all human T-lymphotropic virus type 1 (HTLV-1)-infected persons will develop a disabling inflammatory disease of the central nervous system known as HTLV-1-associated myelopathy/tropical spastic paraparesis, against which there is currently no efficient treatment. As correlation exists between the proviral load (PVL) and the clinical status of the carrier, it is thought that diminishing the PVL could prevent later occurrence of the disease. We have conducted a study combining valproate, an inhibitor of histone deacetylases, and azidothymidine, an inhibitor of reverse transcriptase, in a series of baboons naturally infected with simian T-lymphotropic virus type 1 (STLV-1), whose PVL was equivalent to that of HTLV-1 asymptomatic carriers. We show that the combination of drugs caused a strong decrease in the PVL and prevented the transient rise in PVL that is seen after treatment with histone deacetylases alone. We then demonstrate that the PVL decline was associated with an increase in the STLV-1-specific cytotoxic T-cell population. We conclude that combined treatment with valproate to induce viral expression and azidothymidine to prevent viral propagation is a safe and effective means to decrease PVL in vivo. Such treatments may be useful to reduce the risk of HAM/TSP in asymptomatic carriers with a high PVL.


Asunto(s)
Antivirales/administración & dosificación , Infecciones por Deltaretrovirus/veterinaria , Inhibidores de Histona Desacetilasas/administración & dosificación , Enfermedades de los Monos/tratamiento farmacológico , Papio , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Virus Linfotrópico T Tipo 1 de los Simios , Animales , Terapia Antirretroviral Altamente Activa , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Infecciones por Deltaretrovirus/tratamiento farmacológico , Infecciones por Deltaretrovirus/inmunología , Infecciones por Deltaretrovirus/virología , Modelos Animales de Enfermedad , Quimioterapia Combinada , Femenino , Infecciones por HTLV-I/tratamiento farmacológico , Infecciones por HTLV-I/virología , Humanos , Masculino , Enfermedades de los Monos/inmunología , Enfermedades de los Monos/virología , Paraparesia Espástica Tropical/tratamiento farmacológico , Paraparesia Espástica Tropical/virología , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Ácido Valproico/administración & dosificación , Carga Viral/efectos de los fármacos , Zidovudina/administración & dosificación
14.
Microbiol Spectr ; 10(5): e0298922, 2022 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-36040168

RESUMEN

Zika virus (ZIKV) is a mosquito-borne flavivirus that emerged in the Pacific islands in 2007 and spread to the Americas in 2015. The infection remains asymptomatic in most cases but can be associated with severe neurological disorders. Despite massive efforts, no specific drug or vaccine against ZIKV infection is available to date. Claudins are tight-junction proteins that favor the entry of several flaviviruses, including ZIKV. In this study, we identified two peptides derived from the N-terminal sequences of claudin-7 and claudin-1, named CL7.1 and CL1.1, respectively, that inhibited ZIKV infection in a panel of human cell lines. Using cell-to-cell fusion assays, we demonstrated that these peptides blocked the ZIKV E-mediated membrane fusion. A comparison of the antiviral efficacy of CL1.1 and CL7.1 pointed to the importance of the peptide amphipathicity. Electron microscopic analysis revealed that CL1.1 altered the ultrastructure of the viral particles likely by binding the virus lipid envelope. However, amphipathicity could not fully explain the antiviral activity of CL1.1. In silico docking simulations suggested that CL1.1 may also interact with the E protein, near its stem region. Overall, our data suggested that claudin-derived peptides inhibition may be linked to simultaneous interaction with the E protein and the viral lipid envelope. Finally, we found that CL1.1 also blocked infection by yellow fever and Japanese encephalitis viruses but not by HIV-1 or SARS-CoV-2. Our results provide a basis for the future development of therapeutics against a wide range of endemic and emerging flaviviruses. IMPORTANCE Zika virus (ZIKV) is a flavivirus transmitted by mosquito bites that have spread to the Pacific Islands and the Americas over the past decade. The infection remains asymptomatic in most cases but can cause severe neurological disorders. ZIKV is a major public health threat in areas of endemicity, and there is currently no specific antiviral drug or vaccine available. We identified two antiviral peptides deriving from the N-terminal sequences of claudin-7 and claudin-1 with the latter being the most effective. These peptides block the envelope-mediated membrane fusion. Our data suggested that the inhibition was likely achieved by simultaneously interacting with the viral lipid envelope and the E protein. The peptides also inhibited other flaviviruses. These results could provide the basis for the development of therapies that might target a wide array of flaviviruses from current epidemics and possibly future emergences.


Asunto(s)
Claudinas , Fusión de Membrana , Infección por el Virus Zika , Virus Zika , Humanos , Antivirales/farmacología , Claudina-1 , Lípidos , Péptidos/farmacología , Infección por el Virus Zika/tratamiento farmacológico
15.
PLoS Pathog ; 5(7): e1000521, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19609363

RESUMEN

Nuclear factor (NF)-kappaB is a major survival pathway engaged by the Human T-Lymphotropic Virus type 1 (HTLV-1) Tax protein. Tax1 activation of NF-kappaB occurs predominantly in the cytoplasm, where Tax1 binds NF-kappaB Essential Modulator (NEMO/IKKgamma) and triggers the activation of IkappaB kinases. Several independent studies have shown that Tax1-mediated NF-kappaB activation is dependent on Tax1 ubiquitination. Here, we identify by co-immunoprecipitation assays NEMO-Related Protein (NRP/Optineurin) as a binding partner for Tax1 in HTLV-1 infected and Tax1/NRP co-expressing cells. Immunofluorescence studies reveal that Tax1, NRP and NEMO colocalize in Golgi-associated structures. The interaction between Tax1 and NRP requires the ubiquitin-binding activity of NRP and the ubiquitination sites of Tax1. In addition, we observe that NRP increases the ubiquitination of Tax1 along with Tax1-dependent NF-kappaB signaling. Surprisingly, we find that in addition to Tax1, NRP interacts cooperatively with the Tax1 binding protein TAX1BP1, and that NRP and TAX1BP1 cooperate to modulate Tax1 ubiquitination and NF-kappaB activation. Our data strongly suggest for the first time that NRP is a critical adaptor that regulates the assembly of TAX1BP1 and post-translationally modified forms of Tax1, leading to sustained NF-kappaB activation.


Asunto(s)
Productos del Gen tax/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , FN-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Factor de Transcripción TFIIIA/metabolismo , Sitios de Unión , Proteínas de Ciclo Celular , Línea Celular Tumoral , Productos del Gen tax/genética , Aparato de Golgi , Células HeLa , Humanos , Inmunoprecipitación , Espacio Intracelular/metabolismo , Proteínas de Transporte de Membrana , Dominios y Motivos de Interacción de Proteínas , Técnicas del Sistema de Dos Híbridos , Ubiquitinación
16.
PLoS One ; 16(6): e0252595, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34086776

RESUMEN

Japanese encephalitis virus (JEV) is the major cause of viral encephalitis in South East Asia. It has been suggested that, as a consequence of the inflammatory process during JEV infection, there is disruption of the blood-brain barrier (BBB) tight junctions that in turn allows the virus access to the central nervous system (CNS). However, what happens at early times of JEV contact with the BBB is poorly understood. In the present work, we evaluated the ability of both a virulent and a vaccine strain of JEV (JEV RP9 and SA14-14-2, respectively) to cross an in vitro human BBB model. Using this system, we demonstrated that both JEV RP9 and SA14-14-2 are able to cross the BBB without disrupting it at early times post viral addition. Furthermore, we find that almost 10 times more RP9 infectious particles than SA14-14 cross the model BBB, indicating this BBB model discriminates between the virulent RP9 and the vaccine SA14-14-2 strains of JEV. Beyond contributing to the understanding of early events in JEV neuroinvasion, we demonstrate this in vitro BBB model can be used as a system to study the viral determinants of JEV neuroinvasiveness and the molecular mechanisms by which this flavivirus crosses the BBB during early times of neuroinvasion.


Asunto(s)
Barrera Hematoencefálica/virología , Virus de la Encefalitis Japonesa (Especie)/fisiología , Modelos Biológicos , Barrera Hematoencefálica/fisiología , Línea Celular , Virus de la Encefalitis Japonesa (Especie)/genética , Virus de la Encefalitis Japonesa (Especie)/patogenicidad , Encefalitis Japonesa/patología , Encefalitis Japonesa/virología , Células Endoteliales/citología , Células Endoteliales/metabolismo , Células Endoteliales/virología , Humanos , ARN Viral/genética , ARN Viral/metabolismo , Virulencia , Replicación Viral
17.
Front Microbiol ; 12: 746589, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34616388

RESUMEN

Zika virus (ZIKV) infection has been associated with a series of neurological pathologies. In patients with ZIKV-induced neurological disorders, the virus is detectable in the central nervous system. Thus, ZIKV is capable of neuroinvasion, presumably through infection of the endothelial cells that constitute the blood-brain barrier (BBB). We demonstrate that susceptibility of BBB endothelial cells to ZIKV infection is modulated by the expression of tight-junction protein claudin-7 (CLDN7). Downregulation of CLDN7 reduced viral RNA yield, viral protein production, and release of infectious viral particles in several endothelial cell types, but not in epithelial cells, indicating that CLDN7 implication in viral infection is cell-type specific. The proviral activity of CLDN7 in endothelial cells is ZIKV-specific since related flaviviruses were not affected by CLDN7 downregulation. Together, our data suggest that CLDN7 facilitates ZIKV infection in endothelial cells at a post-internalization stage and prior to RNA production. Our work contributes to a better understanding of the mechanisms exploited by ZIKV to efficiently infect and replicate in endothelial cells and thus of its ability to cross the BBB.

18.
Viruses ; 13(2)2021 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-33503816

RESUMEN

Human herpesvirus 8 (HHV-8) is the etiological agent of all forms of Kaposi's sarcoma (KS). K1 gene studies have identified five major molecular genotypes with geographical clustering. This study described the epidemiology of HHV-8 and its molecular diversity in Gabon among Bantu and Pygmy adult rural populations and KS patients. Plasma antibodies against latency-associated nuclear antigens (LANA) were searched by indirect immunofluorescence. Buffy coat DNA samples were subjected to polymerase chain reaction (PCR) to obtain a K1 gene fragment. We studied 1020 persons; 91% were Bantus and 9% Pygmies. HHV-8 seroprevalence was 48.3% and 36.5% at the 1:40 and 1:160 dilution thresholds, respectively, although the seroprevalence of HHV-8 is probably higher in Gabon. These seroprevalences did not differ by sex, age, ethnicity or province. The detection rate of HHV-8 K1 sequence was 2.6% by PCR. Most of the 31 HHV-8 strains belonged to the B genotype (24), while the remaining clustered within the A5 subgroup (6) and one belonged to the F genotype. Additionally, we reviewed the K1 molecular diversity of published HHV-8 strains in Africa. This study demonstrated a high seroprevalence of HHV-8 in rural adult populations in Gabon and the presence of genetically diverse strains with B, A and also F genotypes.


Asunto(s)
Herpesvirus Humano 8/genética , Sarcoma de Kaposi/epidemiología , Sarcoma de Kaposi/virología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/sangre , Antígenos Virales/inmunología , ADN Viral/genética , Femenino , Gabón/epidemiología , Variación Genética , Genotipo , Herpesvirus Humano 8/clasificación , Herpesvirus Humano 8/inmunología , Herpesvirus Humano 8/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Proteínas Nucleares/inmunología , Filogenia , Población Rural , Estudios Seroepidemiológicos , Proteínas Virales/genética , Adulto Joven
19.
J Virol ; 83(10): 5244-55, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19279090

RESUMEN

Little is known about the transmission or tropism of the newly discovered human retrovirus, human T-cell lymphotropic virus type 3 (HTLV-3). Here, we examine the entry requirements of HTLV-3 using independently expressed Env proteins. We observed that HTLV-3 surface glycoprotein (SU) binds efficiently to both activated CD4(+) and CD8(+) T cells. This contrasts with both HTLV-1 SU, which primarily binds to activated CD4(+) T cells, and HTLV-2 SU, which primarily binds to activated CD8(+) T cells. Binding studies with heparan sulfate proteoglycans (HSPGs) and neuropilin-1 (NRP-1), two molecules important for HTLV-1 entry, revealed that these molecules also enhance HTLV-3 SU binding. However, unlike HTLV-1 SU, HTLV-3 SU can bind efficiently in the absence of both HSPGs and NRP-1. Studies of entry performed with HTLV-3 Env-pseudotyped viruses together with SU binding studies revealed that, for HTLV-1, glucose transporter 1 (GLUT-1) functions at a postbinding step during HTLV-3 Env-mediated entry. Further studies revealed that HTLV-3 SU binds efficiently to naive CD4(+) T cells, which do not bind either HTLV-1 or HTLV-2 SU and do not express detectable levels of HSPGs, NRP-1, and GLUT-1. These results indicate that the complex of receptor molecules used by HTLV-3 to bind to primary T lymphocytes differs from that of both HTLV-1 and HTLV-2.


Asunto(s)
Antígenos de Deltaretrovirus/metabolismo , Deltaretrovirus/metabolismo , Productos del Gen env/metabolismo , Receptores Virales/metabolismo , Secuencia de Aminoácidos , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/virología , Línea Celular , Deltaretrovirus/genética , Deltaretrovirus/fisiología , Transportador de Glucosa de Tipo 1/metabolismo , Proteoglicanos de Heparán Sulfato/metabolismo , Humanos , Datos de Secuencia Molecular , Filogenia , Unión Proteica , Alineación de Secuencia , Transducción Genética , Acoplamiento Viral
20.
PLoS Pathog ; 4(11): e1000205, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19008946

RESUMEN

The blood-brain barrier (BBB), which forms the interface between the blood and the cerebral parenchyma, has been shown to be disrupted during retroviral-associated neuromyelopathies. Human T Lymphotropic Virus (HTLV-1) Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a slowly progressive neurodegenerative disease associated with BBB breakdown. The BBB is composed of three cell types: endothelial cells, pericytes and astrocytes. Although astrocytes have been shown to be infected by HTLV-1, until now, little was known about the susceptibility of BBB endothelial cells to HTLV-1 infection and the impact of such an infection on BBB function. We first demonstrated that human cerebral endothelial cells express the receptors for HTLV-1 (GLUT-1, Neuropilin-1 and heparan sulfate proteoglycans), both in vitro, in a human cerebral endothelial cell line, and ex vivo, on spinal cord autopsy sections from HAM/TSP and non-infected control cases. In situ hybridization revealed HTLV-1 transcripts associated with the vasculature in HAM/TSP. We were able to confirm that the endothelial cells could be productively infected in vitro by HTLV-1 and that blocking of either HSPGs, Neuropilin 1 or Glut1 inhibits this process. The expression of the tight-junction proteins within the HTLV-1 infected endothelial cells was altered. These cells were no longer able to form a functional barrier, since BBB permeability and lymphocyte passage through the monolayer of endothelial cells were increased. This work constitutes the first report of susceptibility of human cerebral endothelial cells to HTLV-1 infection, with implications for HTLV-1 passage through the BBB and subsequent deregulation of the central nervous system homeostasis. We propose that the susceptibility of cerebral endothelial cells to retroviral infection and subsequent BBB dysfunction is an important aspect of HAM/TSP pathogenesis and should be considered in the design of future therapeutics strategies.


Asunto(s)
Barrera Hematoencefálica/patología , Barrera Hematoencefálica/virología , Virus Linfotrópico T Tipo 1 Humano , Paraparesia Espástica Tropical/patología , Infecciones por Retroviridae/patología , Autopsia , Línea Celular , Células Endoteliales/patología , Células Endoteliales/virología , Humanos , Receptores Virales/análisis , Médula Espinal/patología , Uniones Estrechas/patología , Uniones Estrechas/virología
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