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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.

International audience; 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.

International audience; Human T-cell leukemia/lymphoma virus-1 (HTLV-1), the first human oncoretrovirus, is the etiological agent of a chronic neuromyelopathy named “tropical spastic paraparesis/HTLV-1–associated myelopathy (TSP/HAM). At least 5–10 million individuals are infected worldwide. The areas of highest prevalence are southwestern Japan and parts of the Caribbean, South America, intertropical Africa, and the Middle East. The lifetime risk of developing TSP/HAM in HTLV-1 carriers is estimated at 0.25–4%, depending on the endemic area. The neurological characteristics include spasticity or hyper-reflexia of the lower limbs, urinary bladder disturbances often with lower limb muscle weakness, sensory disturbance, and low back pain. TSP/HAM pathology is characterized by chronic inflammation with perivascular lymphocyte cuffs and mild parenchymal lymphocytic infiltrates, foamy macrophages, astrocyte proliferation, and fibrillary gliosis. Pyramidal tract degenerative lesions with myelin and axonal loss are observed, mainly in the lower thoracic spinal cord; these are linked to inflammatory foci in the CNS. The treatment of TSP/HAM remains largely symptomatic because there is no current disease-modifying therapy with definite long-term clinical benefit.

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).

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.

Human herpesvirus 8 (HHV-8) is the etiological agent of all forms of Kaposi&rsquo, 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.

HIV-1 can cross the blood-brain barrier (BBB) to penetrate the brain and infect target cells, causing neurocognitive disorders as a result of neuroinflammation and brain damage. The HIV-1 envelope spike gp160 is partially required for viral transcytosis across the BBB endothelium. But do antibodies developing in infected individuals and targeting the HIV-1 gp160 glycoproteins block HIV-1 transcytosis through the BBB? We addressed this issue and discovered that anti-gp160 antibodies do not block HIV-1 transport; instead, free viruses and those in complex with antibodies can transit across BBB endothelial cells. Importantly, we found that only neutralizing antibodies could inhibit posttranscytosis viral infectivity, highlighting their ability to protect susceptible brain cells from HIV-1 infection., HIV-1 can cross the blood-brain barrier (BBB) to penetrate the brain and infect target cells, causing neurocognitive disorders as a result of neuroinflammation and brain damage. Here, we examined whether antibodies targeting the HIV-1 envelope glycoproteins interfere with the transcytosis of virions across the human BBB endothelium. We found that although the viral envelope spike gp160 is required for optimal endothelial cell endocytosis, no anti-gp160 antibodies blocked the BBB transcytosis of HIV-1 in vitro. Instead, both free viruses and those in complex with antibodies transited across endothelial cells in the BBB model, as observed by confocal microscopy. HIV-1 infectious capacity was considerably altered by the transcytosis process but still detectable, even in the presence of nonneutralizing antibodies. Only virions bound by neutralizing antibodies lacked posttranscytosis infectivity. Overall, our data support the role of neutralizing antibodies in protecting susceptible brain cells from HIV-1 infection despite their inability to inhibit viral BBB endocytic transport.

Africa is the largest known endemic area for HTLV-1, with a high diversity of molecular genotypes. We previously demonstrated that some HTLV-1 strains from North Africa (the a-NA clade) are the result of a recombinant event between Senegalese and West African strains. To better characterize these recombinants and their distribution, we sequenced the LTR region and/or a env gene fragment of a series of 52 HTLV-1 strains from 13 different countries in North and West Africa. Four samples from descendants of African slaves and native to French Guiana were also added. Furthermore, we characterized the complete sequence for 7 viral strains, from the different genotypes. Until now, no complete sequence was available for a-NA clade. Phylogenetic analysis demonstrates that most of the new African strains belong to the Cosmopolitan a-genotype. Ten new strains from the recombinant North African (a-NA) clade could be found in Morocco, Western Sahara, Mali, Guinea, Côte d'Ivoire, and Ghana. We also identified a new clade (named a-G-Rec) comprising 4 strains from Guinea and Ghana that arose from a distinct recombination event between strains from Senegal and West Africa. The analyses of complete sequences suggest that recombination does not only occur in the LTR but also in other regions (env/pol) of the genome. Our data strongly suggest that a-NA and a-G-Rec strains have a mosaic profile with genetic segments deriving from either a-WA or a-Sen strains. In conclusion, our work demonstrates that recombination in HTLV-1 may not be such a rare event as previously proposed.

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.

Muscle cells are potential targets of many arboviruses, such as Ross River, Dengue, Sindbis, and chikungunya viruses, that may be involved in the physiopathological course of the infection. During the recent outbreak of Zika virus (ZIKV), myalgia was one of the most frequently reported symptoms. We investigated the susceptibility of human muscle cells to ZIKV infection. Using an in vitro model of human primary myoblasts that can be differentiated into myotubes, we found that myoblasts can be productively infected by ZIKV. In contrast, myotubes were shown to be resistant to ZIKV infection, suggesting a differentiation-dependent susceptibility. Infection was accompanied by a caspase-independent cytopathic effect, associated with paraptosis-like cytoplasmic vacuolization. Proteomic profiling was performed 24h and 48h post-infection in cells infected with two different isolates. Proteome changes indicate that ZIKV infection induces an upregulation of proteins involved in the activation of the Interferon type I pathway, and a downregulation of protein synthesis. This work constitutes the first observation of primary human muscle cells susceptibility to ZIKV infection, and differentiation-dependent restriction of infection from myoblasts to myotubes. Since myoblasts constitute the reservoir of stem cells involved in reparation/regeneration in muscle tissue, the infection of muscle cells and the viral-induced alterations observed here could have consequences in ZIKV infection pathogenesis., Author summary Muscle cells are potential targets of many arboviruses, such as Ross River, Dengue, Sindbis, and chikungunya viruses, and may be involved in the disease manifestation. During the recent outbreak of Zika virus (ZIKV), myalgia was one of the most frequently reported symptoms. We investigated the susceptibility of human muscle cells to ZIKV infection. Using an in vitro model of human muscle stem cells (myoblasts) that can be differentiated into differentiated muscle cells (myotubes), we found that myoblasts can be infected by ZIKV. In contrast, myotubes were shown to be resistant to ZIKV infection. Infection induced the death of infected cells. Protein levels 24h and 48h post-infection indicate that ZIKV infection induces an upregulation of proteins involved in the activation of the Interferon type I pathway, and a downregulation of protein synthesis. This work constitutes the first observation of primary human muscle cells susceptibility to ZIKV infection, muscle stem cells being susceptible while differentiated muscle cells are resistant. Since myoblasts constitute the reservoir of stem cells involved in reparation/regeneration in muscle tissue, the infection of muscle cells and the viral-induced alterations observed here could have consequences during ZIKV infection.

Among all known retroviruses, foamy viruses (FVs) have the most stable virus–host co-speciation history, co-diverging in concert with their vertebrate hosts for hundreds of millions of years. However, detailed molecular analyses indicate that different parts of their genome might have different evolutionary histories. While their polymerase gene displays a robust and straightforward virus–host co-speciation pattern, the evolutionary history of their envelope (env) gene, is much more complicated. Here, we report eleven new FV env sequences in two mandrill populations in Central Africa, geographically separated by the Ogooué River into the North and the South populations. Phylogenetic reconstruction of the polymerase gene shows that the two virus populations are distinct, and each contains two variants of env genes co-existing with one another. The distinction between the two env variants can be mapped to the surface domain, flanked by two recombination hotspots, as previously reported for chimpanzee and gorilla FVs. Our analyses suggest that the two env variants originated during the diversification of Old World monkeys and apes, ∼30 million years ago. We also show that this env gene region forms two phylogenetically distinct clades, each displaying a host co-divergence and geographical separation pattern, while the rest of the genome of the two strains is phylogenetically indistinguishable in each of the host-specific groups. We propose possible evolutionary mechanisms to explain the modular nature of the FV genome.

Japanese encephalitis virus (JEV) is the major cause of viral encephalitis in South East Asia. It has been suggested that JEV gets access to the central nervous system (CNS) as a consequence of a preceding inflammatory process which leads to the blood-brain barrier (BBB) disruption and viral neuroinvasion. 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 anin cellulohuman BBB model consisting of hCMEC/D3 human endothelial cells cultivated on permeable inserts above SK-N-SH human neuroblastoma cells. 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-addition. Furthermore, this BBB model was able to discriminate between the virulent RP9 and the vaccine SA14-14-2 strains, as demonstrated by the presence of almost 10 times more RP9 infectious particles that crossed the BBB than SA14-14 particles at a high MOI. Besides contributing to the understanding of early events in JEV neuroinvasion, thisin celluloBBB model represents a suitable and useful system to study the viral determinants of JEV neuroinvasiveness and the molecular mechanisms by which this flavivirus crosses the BBB at early times of neuroinvasion.

International audience; The early screening of nervous system medicines on a pertinent and reliable in cellulo BBB model for their penetration and their interaction with the barrier and the brain parenchyma is still an unmet need. To fill this gap, we designed a 2D in cellulo model, the BBB-Minibrain, by combining a polyester porous membrane culture insert human BBB model with a Minibrain formed by a tri-culture of human brain cells (neurons, astrocytes and microglial cells). The BBB-Minibrain allowed us to test the transport of a neuroprotective drug candidate (e.g., Neurovita), through the BBB, to determine the specific targeting of this molecule to neurons and to show that the neuroprotective property of the drug was preserved after the drug had crossed the BBB. We have also demonstrated that BBB-Minibrain constitutes an interesting model to detect the passage of virus particles across the endothelial cells barrier and to monitor the infection of the Minibrain by neuroinvasive virus particles. The BBB-Minibrain is a reliable system, easy to handle for researcher trained in cell culture technology and predictive of the brain cells phenotypes after treatment or insult. The interest of such in cellulo testing would be twofold: introducing derisking steps early in the drug development on the one hand and reducing the use of animal testing on the other hand.

Background Primate T-lymphotropic viruses type 1 (PTLV-1) are complex retroviruses infecting both human (HTLV-1) and simian (STLV-1) hosts. They share common epidemiological, clinical and molecular features. In addition to the canonical gag, pol, env retroviral genes, PTLV-1 purportedly encodes regulatory (i.e. Tax, Rex, and HBZ) and accessory proteins (i.e. P12/8, P13, P30). The latter have been found essential for viral persistence in vivo. Methodology/Principal findings We have isolated a STLV-1 virus from a bonnet macaque (Macaca radiata–Mra18C9), a monkey from India. The complete sequence was obtained and phylogenetic analyses were performed. The Mra18C9 strain is highly divergent from the known PTLV-1 strains. Intriguingly, the Mra18C9 lacks the 3 accessory open reading frames. In order to determine if the absence of accessory proteins is specific to this particular strain, a comprehensive analysis of the complete PTLV-1 genomes available in Genbank was performed and found that the lack of one or many accessory ORF is common among PTLV-1. Conclusion This study raises many questions regarding the actual nature, role and importance of accessory proteins in the PTLV-1 biology., Author summary Primate T-lymphotropic viruses type 1 (PTLV-1) are complex retroviruses infecting both human (HTLV-1) and simian (STLV-1) hosts. It has been shown that the persistence and pathogenesis of these viruses depend on the expression of small, accessory proteins. A bonnet macaque (a monkey present in India) was found infected with STLV-1. The genome was sequenced and found quite divergent from the other STLV-1 genomes previously described. Intriguingly, this virus does not encode accessory proteins. Analysis of other available sequences found that most strains lack at least one accessory gene. Thus the importance and the role of these proteins in the PTLV-1 biology should be revisited.

Extracellular vesicles (EVs) can participate in intercellular communication and pathogenesis. EVs contain many cargos, including proteins, and the composition of EVs differs between cell-types and activation levels. Thus, plasma EVs can be used as a biomarker of systemic response to infection and/or disease progression. In this study, we aimed at describing alterations in the protein content of plasma EVs upon infection with the human T-lymphotropic retrovirus type 1 (HTLV-1). HTLV-1 is the etiological agent of a lymphoproliferative disease (ATL) and a series of inflammatory diseases, including a neurodegenerative inflammatory disease (HAM/TSP). We found that plasma EVs are more abundant and smaller in HTLV-1 asymptomatic carriers or HAM/TSP patients when compared to uninfected healthy donors. Moreover, EVs from HTLV-1 infected donors contain markers of metabolic and mitochondrial stress.

Two human retroviruses, human T-cell lymphotropic virus type 1 (HTLV-1) and human immunodeficiency virus type 1 (HIV-1), are associated with central nervous system (CNS) infections and subsequent neurological disorders. HTLV-1 is the etiological agent of a neuroinflammatory disease, the tropical spastic paraparesis or HTLV-1-associated myelopathy (HAM/TSP), whereas HIV-1 induces HIV-associated dementia (HAD). With both infections, the blood-brain barrier (BBB) between the CNS and the blood is disrupted. Several cellular or viral factors are involved in this process, such as proinflammatory cytokines, matrix metalloproteinases, or viral proteins. BBB disruption can also be triggered by retroviral infection of BBB components such as endothelial cells. Moreover, interactions of retroviruses with the BBB modify the expression of surface proteins on the BBB, leading to the passage of retroviruses through the BBB, either as free viral particles or as infected cells. Yet current retroviral treatments hardly penetrate the CNS and treatment of CNS infections by retroviruses remains a major concern.

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.

De novo pyrimidine biosynthesis is a key metabolic pathway involved in multiple biosynthetic processes. Here, we identified an original series of 3-(1 H -indol-3-yl)-2,3-dihydro-4 H -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.

International audience; 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.

International audience; Human T-cell Lymphotropic Virus type 1 (HTLV-1) is a human retrovirus that infects at least 5–10 million people worldwide, and is the etiological agent of a lymphoproliferative malignancy; Adult T-cell Leukemia/Lymphoma (ATLL); and a chronic neuromyelopathy, HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP), as well as other inflammatory diseases such as infective dermatitis and uveitis. Besides sexual intercourse and intravenous transmission, HTLV-1 can also be transmitted from infected mother to child during prolonged breastfeeding. Some characteristics that are linked to mother-to-child transmission (MTCT) of HTLV-1, such as the role of proviral load, antibody titer of the infected mother, and duration of breastfeeding, have been elucidated; however, most of the mechanisms underlying HTLV-1 transmission during breast feeding remain largely unknown, such as the sites of infection and cellular targets as well as the role of milk factors. The present review focuses on the latest findings and current opinions and perspectives on MTCT of HTLV-1.

International audience; Homeostasis in the central nervous system (CNS) is maintained by active interfaces between the bloodstream and the brain parenchyma. The blood-brain barrier (BBB) constitutes a selective filter for exchange of water, solutes, nutrients, and controls toxic compounds or pathogens entry. Some parasites, bacteria, and viruses have however developed various CNS invasion strategies, and can bypass the brain barriers. Concerning viruses, these strategies include transport along neural pathways, transcytosis, infection of the brain endothelial cells, breaching of the BBB, and passage of infected-leukocytes. Moreover, neurotropic viruses can alter BBB functions, thus compromising CNS homeostasis. Retroviruses have been associated to human neurological diseases: HIV (human immunodeficiency virus 1) can induce HIV-associated dementia, and HTLV-1 (human T lymphotropic virus 1) is the etiological factor of tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). The present review focuses on how the different retroviruses interact with this structure, bypass it and alter its functions.

The blood-brain barrier (BBB), which constitutes the interface between blood and cerebral parenchyma, has been shown to be disrupted during retroviral associated neuromyelopathies. Human T cell leukemia virus (HTLV-1)-associated myelopathy/tropical spastic paraparesis is a slowly progressive neurodegenerative disease, in which evidence of BBB breakdown has been demonstrated by the presence of lymphocytic infiltrates in the CNS and plasma protein leakage through cerebral endothelium. Using an in vitro human BBB model, we investigated the cellular and molecular mechanisms involved in endothelial changes induced by HTLV-1-infected lymphocytes. We demonstrate that coculture with infected lymphocytes induces an increase in paracellular endothelial permeability and transcellular migration, via IL-1α and TNF-α secretion. This disruption is associated with tight junction disorganization between endothelial cells, and alterations in the expression pattern of tight junction proteins such as zonula occludens 1. These changes could be prevented by inhibition of the NF-κB pathway or of myosin light chain kinase activity. Such disorganization was confirmed in histological sections of spinal cord from an HTLV-1-associated myelopathy/tropical spastic paraparesis patient. Based on this BBB model, the present data indicate that HTLV-1-infected lymphocytes can induce BBB breakdown and may be responsible for the CNS infiltration that occurs in the early steps of retroviral-associated neuromyelopathies.

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.

The HTLV-1 transactivator protein Tax controls many critical cellular pathways including host cell DNA damage response mechanisms, cell cycle progression, and apoptosis. Recently, exosomes have been shown to play critical roles during pathogenic viral infections as delivery vehicles for host and viral components including proteins, mRNA and miRNA. We hypothesized that exosomes derived from HTLV-1 infected cells contain unique host and viral proteins that may contribute to pathogenesis. We have characterized exosomes released from uninfected and HTLV-1 infected cell lines, as well as ATL and HAM/TSP material. The functional impact of exosomes derived from HTLV-1 infected cells on naive recipient cells was evaluated by utilizing transcription and reactive oxygen species (ROS) assays. Exosomes from HTLV-1 infected cells displayed unique proteomic profiles distinct from exosomes derived from uninfected cells. For instance, proinflammatory mediators are contained within the exosomes, as well as viral mRNA transcripts including Tax, HBZ, and Env. We found that exosomes from infected cells deliver functional Tax to naA¯ve recipient cells as well as cytokines. The release of factors was through Calcium and Calcium channels. We observed that exosomes released from HTLV-1 infected, Tax-expressing cells contributed to enhanced survival of target cells treated with α-FAS. Two other critical proteins were found in these exosomes that could contribute to overall activation of neighboring cells including Tax1BP1 and PrP. Both proteins are critical for activation of NFkB patway in recipient cells. Collectively, our results suggest that exosomes may play an important role in extracellular delivery of functional HTLV-1 proteins and mRNA to recipient cells. Furthermore, exosomes derived from infected cells are capable of inducing an ROS response in naA¯ve cells and contribute to an anti-apoptotic phenotype in cells treated with α-FAS.

HAM/TSP is a neurodegenerative disease that develops upon infiltration of HTLV-1-infected lymphocytes into the central nervous system (CNS). Physiologically, the CNS is protected and isolated from the immune system by a structure called blood-brain barrier (BBB). Thus HTLV-1-infected lymphocytes have the capacity to cross the blood-brain barrier (BBB). The mechanisms of such crossing are still poorly understood. In the context of multiple sclerosis and neuro-AIDS, the Activated Leukocyte Cell Adhesion Molecule (ALCAM) was shown to amplify leukocyte extravasation. In the earlier, ALCAM is over expressed on the BBB endothelium, whereas in the latter ALCAM expression is increased on HIV-1-infected monocytes. We therefore studied the possible role of ALCAM in extravasation of HTLV-1 infected lymphocytes. We demonstrated by FACS that ALCAM is over expressed both on HTLV-1-infected lymphocytes cell lines and on primary cells from HTLV-1 asymptomatic carriers or HAM/TSP patients. Via transduction with a Tax-encoding lentiviral vectors, we showed that ALCAM over expression is the consequence of Tax-1-induced NF-κB pathway activation. We finally demonstrated that inhibiting ALCAM with a monoclonal blocking antibody reduces significantly the extravasation of HTLV-1 chronically infected cells through a monolayer of BBB endothelial cells (the hCMEC/D3 model). This study reports a potential role of HTLV-1-induced ALCAM overpression in HAM/TSP pathogenesis.

Isolated HTLV-1 viral particles are poorly infectious both in vivo and in vitro. In contrast, the virus is efficiently transmitted through cell-to-cell contact. While the molecular mechanisms of viral cell-to-cell propagation have been extensively studied, the mechanisms facilitating the encounter between an infected cell and a target cell remain unknown. We postulated that the infected cells could behave as a source of chemoattractant, thus recruiting target cells. In 2012, Trindade et al. showed that PBMCs from HTLV-1 infected individuals (HTLV-1 asymptomatic carrier and HAM/TSP patients) could secrete higher levels of leukotriene B4 (LTB4), a potent chemoattractant, than cells from healthy donors. We proposed that, although T cells purportedly secrete no LTB4, LTB4 could be secreted by HTLV-1 infected lymphocytes and facilitate cell-to-cell contacts and viral transmission. We showed by ELISA that HTLV-1 infected lymphocytes (both primary CD4+ T cells and chronically infected cell lines) secrete LTB4. By cell transduction with lentiviral vectors encoding Tax, we suggest that HTLV-1 induced LTB4 secretion is a consequence of Tax-induced cytosolic phospholipase A2 (cPLA2) over expression. Blocking LTB4 secretion (with diverse specific inhibitors of the leukotriene pathway) prevented the recruitment of potential target cells, as well as the formation of cell-to-cell contacts. In conclusion, HTLV-1 diverts the leukotriene pathway and LTB4-mediated chemotaxis facilitates viral propagation.

Four types of primate T-cell lymphotropic viruses (PTLVs) have been discovered. While three of them, i.e., PTLV-1, PTLV-2, and PTLV-3, include human T-cell lymphotropic viruses (HTLV-1, HTLV-2, and HTLV-3) and simian T-cell lymphotropic viruses (STLV-1, STLV-2, and STLV-3), the fourth type (HTLV-4) has so far been found to consist only of a unique human isolate (4, 52). STLV-3 (formerly named PTLV-L) was isolated shortly before STLV-2 (14). The STLV-3 lineage is composed of at least two subtypes that correspond more or less to the geographical sources of the isolates (East Africa and west-central Africa) (7, 14, 24, 25, 27, 46, 47, 49, 51). Although STLV-3 is much more widespread than STLV-2 in African monkeys, STLV-3 infection has not been linked to any pathology so far, yet neither longitudinal follow-up nor clinical studies have been performed. Sequence comparisons of STLV-3 full-length proviruses pointed out that these strains are highly divergent from HTLV-1, HTLV-2, and STLV-2 (40%, 38%, and 38% divergence, respectively) (7, 14, 24, 25, 27, 46, 47, 49, 51). The overall STLV-3 genomic organization is similar to that of HTLV-1 and HTLV-2; the gag, pro, pol, env, tax, and rex genes are present (24, 25, 46, 47, 51). Sequence analyses also revealed that STLV-3 long terminal repeat (LTR) sequences possess only two 21-bp repeats (or Tax-responsive elements [TREs]), while HTLV-1 and HTLV-2 LTRs retain three of these sequences (24, 25, 46). The impact of the lack of a TRE on viral transcription is not known. Interestingly, apart from Tax and Rex, the STLV-3 prototype (STLV-3PH969) pX region was reported to contain only one additional open reading frame (ORF) whose corresponding mRNA can be amplified by reverse transcriptase (RT)-PCR (47). This mRNA could be translated into a putative 84-amino-acid-long protein designated RorfII, which shares some similarities with the HTLV-1 p12 protein (47). Of note, the RorfII mRNA was not detected in the two other STLV-3 strains (PPAF3 and CTO604) that have been analyzed lately by RT-PCR. In fact, sequence analysis of these isolates revealed either a mutation in the splice acceptor sequence and/or a stop codon in the RorfII sequence (24, 25). At this point, it is therefore not clear whether, apart from Tax and Rex, additional ORFs are commonly present in the STLV-3 pX sequence. We and others have uncovered the existence of HTLV-3, a third member of the HTLV family, in two Cameroonian individuals (4, 52). We therefore ought to obtain the complete sequence of HTLV-3Pyl43 in order to determine its genomic organization and to characterize its Tax protein. Full-length genome comparisons and phylogenetic analyses allow us to demonstrate that the HTLV-3 genome organization is similar to that of HTLV-1 and HTLV-2 and is related to some central African STLV-3 strains. Like STLV-3, HTLV-3 LTRs contain only two Tax-responsive elements. Unexpectedly, a 366-bp sequence is lacking in the HTLV-3 proximal pX region. This sequence corresponds in part to the RorfII sequence that was previously described for STLV-3PH969 and also to the 3′ end of a putative antisense transcript. We have lately demonstrated that HTLV-3 Tax protein is expressed in vivo (6). Our results now reveal that Tax3Pyl43 is functionally more closely related to the transforming HTLV-1 Tax protein than to HTLV-2 Tax, suggesting that HTLV-3, like HTLV-1, might be pathogenic in vivo.

Although recombination is a major source of genetic variability in retroviruses, no recombinant strain had been observed for 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, including the complete LTR and a 522-bp fragment of the env gene, which we collected from 19 countries throughout North, West and Central Africa, the continent where the virus has the largest endemic presence. The samples were obtained from 41 HTLV-1 infected individuals with different clinical statuses including ATL, TSP/HAM and asymptomatic carriers. The recombinant search and breakpoint detection were performed by boot scanning in Simplot to compare inferred clusters of sequences to each other. Finally, molecular clock analyses were performed to date the recombinant event observed. 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 4,0 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 (Desrames et al., J. Virology, 88, 2014). In order to precise the geographical distribution of this recombinant within the African Continent, we studied a new set of samples from HTLV-1 infected patients of diverse African origin. The data on this on-going study will be presented.

Merkel cell polyomavirus (MCPyV) is linked to a cutaneous cancer mainly occurring in Caucasians. DNA from skin swabs of 255 adults, originating from the 5 continents, were subjected to MCPyV PCRs. Phylogenetic analyses demonstrate the existence of 5 major geographically related MCPyV genotypes (Europe/North America, Africa [sub-Saharan], Oceania, South America, and Asia/Japan).

Background Kaposi's sarcoma associated herpesvirus (KSHV/HHV-8) is the causal agent of all forms of Kaposi sarcoma. Molecular epidemiology of the variable K1 region identified five major subtypes exhibiting a clear geographical clustering. The present study is designed to gain new insights into the KSHV epidemiology and genetic diversity in Cameroon. Methodology/Principal Findings Bantu and Pygmy populations from remote rural villages were studied. Antibodies directed against latent nuclear antigens (LANA) were detected by indirect immunofluorescence using BC3 cells. Peripheral blood cell DNAs were subjected to a nested PCR amplifying a 737 bp K1 gene fragment. Consensus sequences were phylogenetically analyzed. We studied 2,063 persons (967 females, 1,096 males, mean age 39 years), either Bantus (1,276) or Pygmies (787). The Bantu group was older (42 versus 35 years: P, Author Summary Kaposi's sarcoma associated herpesvirus (KSHV/HHV-8) is the causal agent of one of the most frequent skin tumors found endemically or epidemically associated to HIV in Central and Eastern Africa. This highly variable virus tends to cluster geographically according to specific major subtypes. Its prevalence is high in that area and increases with age. Despite its association to all forms of Kaposi sarcoma and high prevalence described in some low income populations in Cameroon, KSHV arouses limited interest, and only few focused previous studies have looked into prevalence and modes of transmission, especially in families. Extended molecular epidemiology is unknown both in healthy individuals and in Kaposi patients, which led to looking for new insights among Bantu and Pygmy populations from rural villages in three regions of Cameroon sharing a quite similar living environment but yet genetically, socially, and culturally different. The present study is designed to describe variations of molecular subtypes in each of these population groups regarding their geography in rural areas of southern, central, and eastern Cameroon.

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., Author Summary HTLV-1 was the first human oncoretrovirus to be discovered. Five to ten million people are infected, and 1–6% will develop either Adult T-cell Leukemia, or Tropical Spastic Paraparesis/HTLV-1 Associated Myelopathy (TSP/HAM). HTLV-1 infects primarily T-cells, but dendritic cells were also found to carry proviruses. Contrary to HIV-1, cell-free HTLV-1 viral particles are poorly infectious. Thus, efficient viral transmission relies on formation of virological synapses or formation and transfer of viral biofilm-like structures. The Tax viral transactivator plays a key role in both modes of transmission. Using transcriptomic analyses, we recently identified cellular genes that are deregulated following Tax expression in T-cells. We focused our attention on genes that are important for cell architecture and are thus likely to modulate cell-to-cell contacts and motility. We found that Gem was highly upregulated both at the RNA and protein levels in Tax-expressing cells and HTLV-1-infected cell lines. We further show that Tax binds cellular co-activators and transcription factor and activates transcription from the gem promoter. We demonstrated that Gem is involved in cellular migration of HTLV-1-infected cells. Importantly, gem knockdown decreases the rate of HTLV-1-infected cell migration and cell-to-cell conjugate formation. We also show that Gem plays an important role in HTLV-1 transmission through cell-to-cell contacts, the most efficient mode of viral infection.

International audience; HTLV-1 infects approximately 5-10 million people worldwide. It is widely distributed, with clusters of high endemicity in certain geographic areas or ethnic groups. Seven main HTLV-1 subtypes have been described and the Melanesian/Australian subtype C is only found in Oceania. In Australia, HTLV-1 is endemic with ATLL, TSP/HAM, bronchiectasis, ID and severe scabies cases reported. However, HTLV-1 clinical significance is debated and only one partial HTLV-1 sequence from an Aboriginal Australian (MSHR-1) is available. Therefore, establishing a large HTLV-1 sequence database is essential for the understanding of the epidemiology and pathogenesis of this virus in Indigenous people. Samples were obtained from 23 HTLV-1 patients originated from four broad geographical and language-based areas. Sequence comparison indicated that the 23 new HTLV-1 LTR and Tax-Gag sequences belong to the subtype C as MSHR-1 strain. Phylogenetic analyses evidenced two main clades (Solomon Islands/Vanuatu versus Australia) within subtype C. Interestingly, the Australian clade can be itself divided into two clusters: the first comprising strains characterized among most of the Indigenous Australians from the North and the second including a majority of individuals originating from the South and Central Australia. Thus, there is a clear evidence of a specific HTLV-1 clustering according to the childhood residence of the HTLV-1 infected individuals, and subsequently their language group affinity. Taking into account that non-human primates have never been found in Australia, we believe that these HTLV-1 subtype C variants have been present among the first ancestors of modern Indigenous Australians for several tens of millennia.

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 defined1,2. Once outside the vessel, individual neutrophils often show extremely coordinated chemotaxis and cluster formation reminiscent of the swarming behaviour of insects3,4,5,6,7,8,9,10,11. 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 migration12, 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.

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.