Increasing importance of European lineages in seeding the hepatitis C virus subtype 1a epidemic in Spain
Ana Belén PérezBram VranckenNatalia ChuecaAntonio AguileraGabriel ReinaMiguel García DeltoroFrancisco Jesús VeraMiguel Angel Von WichmanJuan Ignacio ArenasFrancisco TéllezJuan A. PinedaMohamed OmarEnrique BernalAntónio Rivero‐JuarezElisa Fernández-FuertesAlberto de la IglesiaJ.M. PascasioPhilippe LemeyFéderico GarcíaLize Cuypers
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Abstract:
Background Reducing the burden of the hepatitis C virus (HCV) requires large-scale deployment of intervention programmes, which can be informed by the dynamic pattern of HCV spread. In Spain, ongoing transmission of HCV is mostly fuelled by people who inject drugs (PWID) infected with subtype 1a (HCV1a). Aim Our aim was to map how infections spread within and between populations, which could help formulate more effective intervention programmes to halt the HCV1a epidemic in Spain. Methods Epidemiological links between HCV1a viruses from a convenience sample of 283 patients in Spain, mostly PWID, collected between 2014 and 2016, and 1,317, 1,291 and 1,009 samples collected abroad between 1989 and 2016 were reconstructed using sequences covering the NS3, NS5A and NS5B genes. To efficiently do so, fast maximum likelihood-based tree estimation was coupled to a flexible Bayesian discrete phylogeographic inference method. Results The transmission network structure of the Spanish HCV1a epidemic was shaped by continuous seeding of HCV1a into Spain, almost exclusively from North America and European countries. The latter became increasingly relevant and have dominated in recent times. Export from Spain to other countries in Europe was also strongly supported, although Spain was a net sink for European HCV1a lineages. Spatial reconstructions showed that the epidemic in Spain is diffuse, without large, dominant within-country networks. Conclusion To boost the effectiveness of local intervention efforts, concerted supra-national strategies to control HCV1a transmission are needed, with a strong focus on the most important drivers of ongoing transmission, i.e. PWID and other high-risk populations.Keywords:
Molecular Epidemiology
Purpose of review: Molecular tools have been developed to detect and differentiate Cryptosporidium at the species/genotype and subtype levels. These tools have been increasingly used in the characterization of the transmission of Cryptosporidium spp. This review addresses the most recent developments in molecular epidemiology of cryptosporidiosis. Recent findings: The recent development of subtyping tools has led to better understanding of the population genetics and transmission of Cryptosporidium in humans. The population structure of C. parvum and C. hominis is apparently more complicated than previously suggested, with the likely existence of both clonal and panmictic populations. Thus, the transmission of C. parvum (genotype II) in humans is shown to be different in different areas, with zoonotic transmission important in certain places and anthroponotic transmission in others. The use of molecular tools has also led to the identification of geographic and temporal differences in the transmission of C. parvum and C. hominis, and better appreciation of the public health importance of other Cryptosporidium species/genotypes and the frequency of infections with mixed genotypes or subtypes. Summary: Factors involved in the transmission of human cryptosporidiosis are difficult to examine using conventional methods. The use of molecular tools has been helpful in the assessment of the zoonotic potential of various Cryptosporidium spp. and sources of human infections, and has started to play a significant role in the characterization of transmission dynamic in endemic and epidemic areas.
Subtyping
Molecular Epidemiology
Cryptosporidium parvum
Zoonosis
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Molecular tools have been developed to detect and differentiate Cryptosporidium at the species/genotype and subtype levels. These tools have been increasingly used in the characterization of the transmission of Cryptosporidium spp. This review addresses the most recent developments in molecular epidemiology of cryptosporidiosis.The recent development of subtyping tools has led to better understanding of the population genetics and transmission of Cryptosporidium in humans. The population structure of C. parvum and C. hominis is apparently more complicated than previously suggested, with the likely existence of both clonal and panmictic populations. Thus, the transmission of C. parvum (genotype II) in humans is shown to be different in different areas, with zoonotic transmission important in certain places and anthroponotic transmission in others. The use of molecular tools has also led to the identification of geographic and temporal differences in the transmission of C. parvum and C. hominis, and better appreciation of the public health importance of other Cryptosporidium species/genotypes and the frequency of infections with mixed genotypes or subtypes.Factors involved in the transmission of human cryptosporidiosis are difficult to examine using conventional methods. The use of molecular tools has been helpful in the assessment of the zoonotic potential of various Cryptosporidium spp. and sources of human infections, and has started to play a significant role in the characterization of transmission dynamic in endemic and epidemic areas.
Subtyping
Molecular Epidemiology
Cryptosporidium parvum
Zoonosis
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Lassa virus
Lassa fever
Recombinant virus
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The envelope (E) glycoprotein of JEV is the major antigen to elicit neutralizing antibody (NAb) against JEV infection. In order to develop a rapid and safe neutralization assay system for evaluation of the JEV vaccine strains, we constructed JEV-pseudotyped viruses with JEV env genes (Nakayama-NIH, Beijing-1). The titers of JEV-pseudotyped viruses with NK and BJ strains were 4.0×104 IFU/ml and 1.3×105 IFU/ml in Vero cell cultures, respectively. We have analyzed the neutralization activity of immunized mouse sera with JEV-NK and JEV-BJ pseudotyped viruses. The neutralizing antibody titers of NK and BJ (50% reduction of virus) were about 1:10,000 at each immunized sera. Compared with conventional plaque reduction neutralization test (PRNT), the method using JEV-pseudotyped virus has desirable advantages such as more rapid, easier, and non-biohazardous. This neutralization assay system might be useful to evaluate NAb activity against JEV vaccine strains or vaccine candidates.
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Dengue vaccine
Flavivirus
Attenuated vaccine
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Infectious clone technology provides an opportunity to study the molecular basis of arthropod–virus interactions in detail. This study describes the development of an infectious clone of the prototype yellow fever virus Asibi strain (YFV-As) with the purpose of identifying sequences or domains that influence infection dynamics in the mosquito vector. The full-length cDNA of YFV-As virus was produced from RT-PCR products of parental viral RNA. These were cloned into a low-copy-number plasmid previously used to develop the YFV-17D infectious clone (pACNR/FLYF-17D). Virus recovered from the infectious clone exhibited biological characteristics similar to those of the parental YFV-As, including replication kinetics, reactivity to flavivirus cross-reactive and YFV-specific antibodies and infection and dissemination rates in Aedes aegypti , the principal mosquito vector of YFV. These data provide the basis for future studies with chimeric Asibi/17D viruses to identify the determinants of vaccine attenuation in the vector.
clone (Java method)
Flavivirus
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We read with interest the recent article entitled "Concomitant diagnosis of sexually transmitted infections and human monkeypox in patients attending a sexual health clinic in Milan, Italy" by Rizzo et al.1 in the "Journal of Medical Virology". The recent global outbreaks of human monkeypox virus (mpxv) infections have raised international concerns regarding modes of transmission particularly in developed countries.1, 2 Cases of cutaneous coinfections with herpes simplex, varicella zoster, and human immunodeficiency viruses have been reported.3-10 Our aim is to highlight a novel clinicopathologic observation of concomitant mpxv skin infections with herpes simplex virus and cytomegalovirus in two men. Similar to Rizzo et al. study, this brief communication points to sex as a potential human-to-human mode of transmission of the current outbreak. Multiple viruses may be detected from the lesions of patients with mpox, and therefore a broad workup should be performed in these patients. The first patient was a previously healthy 30-year-old Asian man who presented with a skin rash that started on the penile shaft spreading over the trunk, arms, and face for 10 days. Initially, the skin lesions were asymptomatic then they became itchy, and painful, and were associated with fever, arthralgia, headache, and myalgia. The rash began 2 weeks after having sexual contact. The patient disclosed bisexual sexual behavior of having multiple sexual encounters with multiple different partners. He denied a history of recent travel, contact with animals, insect or rodent bites, drug intake, or similar previous lesions before the current presentation. He sought a private clinic, and was prescribed non-steroid anti-inflammatory drugs and antibiotics for 5 days without improvement. Physical examination revealed several vesicles, pustules, eroded papules, and eschars with erythematous bases scattered over the genitalia, upper trunk, arms, and face (Figure 1A). The palms and soles were free. The patient did not have penile discharge, intraoral or eye lesions, lymphadenopathy, or organomegaly. Clinical differential diagnoses included viral exanthems, syphilis, and drug eruption. Serologic tests were negative for human immunodeficiency virus, cytomegalovirus, and treponema. A repeat serology confirmed the negative status for human immunodeficiency virus. His immune status screen for lymphocytes was normal. Serology revealed positive IgG and IgM for herpes simplex virus type 2. A throat swab test and a sample from the biopsied skin pustule were submitted for virus polymerase chain reaction, which detected mpxv DNA. The patient was treated with intravenous acyclovir, followed for 3 weeks and the rash started to heal. Skin punch biopsy showed a pustular vesicle (Figure 1B). The vesicle revealed acantholytic keratinocytes, some with eosinophilic intracytoplasmic inclusions and others with smudged nuclear inclusions. Typical viral cytopathic changes of herpes infection were partly obscured. Immunohistochemistry demonstrated positive herpes simplex virus inclusions (Figure 1C). The second patient was a 34-year-old heterosexual African man with a history of human immunodeficiency virus infection. He was not on antiretroviral therapy. He denied a history of recent travel. He developed a fever and multiple painful small boils that became indurated crusted lesions on the genitalia, limbs, face, and trunk, which developed 2 weeks after having sexual contact (Figure 2A). He did not have penile discharge, oral or ocular lesions, lymphadenopathy, or organomegaly. His palms and soles were free of skin lesions. Clinical differential diagnoses included viral infections and syphilis. His immune status screen showed a CD4 count of 11.0 cells/µL and a CD4:CD8 ratio of 0.09. Serology revealed positive IgG and IgM for cytomegalovirus, negative for herpes simplex virus and syphilis. He had a blood sample for a polymerase chain reaction that detected CMV DNA. Throat swab and biopsied skin lesion DNA polymerase chain reaction tests were positive for mpxv. The patient succumbed to death due to CMV-related pneumonia, sepsis, and multiple organ failure despite treatment with intravenous ganciclovir. Skin biopsy showed an epidermal pustular vesicle with acantholytic keratinocytes with eosinophilic intracytoplasmic inclusions. Herpes simplex virus immunomarker was negative. The deep dermis also demonstrated vasculitic and dermal inflammatory changes with subtle features suspicious for cytomegalovirus cytopathic changes (Figure 2B). This was confirmed by positive nuclear immunostaining (Figure 2C). Monkeypox is a zoonotic skin infection that starts on the face spreads over the trunk and extremities, involves the palms and soles, and is associated with lymphadenopathy.2 Histologically, the skin lesions show a spongiotic intraepidermal blister with mixed inflammatory infiltrates and eosinophilic intracytoplasmic inclusions in the keratinocytes.11 Occasional multinucleated cells, nuclei with central ground-glass inclusion-like appearance, and follicular involvement may be seen in some cases. Differential diagnoses might include herpes and varicella viruses and other pox viruses.11 Cases of atypical varicella zoster virus skin infections in patients with mpxv infection or from endemic areas have been reported.3, 4 In addition, coinfections between mpox, herpes simplex virus, varicella zoster virus, syphilis, and gonorrhea particularly among HIV-infected homosexual men have been also reported.5-10 This raises a speculated transmission relationship between these viruses, particularly to the current outbreaks.12 The recent outbreaks occurring outside the usual endemic regions of mpxv, most cases were unlinked to recent travel from endemic countries, and the occurrence of multiple clusters may point to a yet undetected chain of possible human-to-human transmission.1, 2, 12 A significant proportion of the reported cases was detected in homosexual men, some from facilities for sexually transmitted diseases.1, 2, 12, 13 The current unusual clinical presentations suggest that mpxv is spreading sexually in certain social groups depending on the routes of virus inoculation.1, 2, 12, 13 Similarly, our cases showed clinical presentations of mpox with simultaneous herpes simplex virus and cytomegalovirus skin coinfections. The patients disclosed sexual contact with multiple partners and developed the rash after sexual intercourse. The rash started on the penis and then spread to the trunks, face, and arms. The skin lesions histologically mimicked herpesvirus skin vesicles in which the characteristic eosinophilic intracytoplasmic inclusions of orthopoxvirus were partly obscured by herpes smudgy nuclear inclusions in the first patient, and by cytomegalovirus vasculitic inflammatory changes in the second patient. Similar to previous reports, our observations point to mpxv infections being sexually transmitted and possibly modified by other virus coinfections, which may mutually be concealed by the superimposed mpxv skin lesions. Serology for acute HSV and CMV is poor.14, 15 IgM is an indicator of recent infection only in subjects who lack detectable IgG.14 Even though IgM detection is a sensitive marker of primary viral infection, but its specificity is poor because IgM may be also produced during viral reactivation and persists following primary infection in some individuals.15 Our patients showed positive serologic tests for both IgM and IgG. This suggests herpes simplex virus and cytomegalovirus reactivation. The fact that they developed the new skin lesions 2 weeks after sexual exposure determines that these individuals were acutely rather than chronically infected with the reactivated viruses. The initial viral cutaneous lesions may serve as entry routes for mpxv during sexual intercourse setting the conditions for simultaneous infections. Because of the possibility of multiple viral skin infections, it is always useful to carry out diagnostic laboratory and instrumental tests to arrive at the correct diagnosis. Noninvasive diagnostics in dermatology has recently made use of new instrumental techniques for the diagnosis of viral skin infections. Using line-field confocal optical coherence tomography, Cortonesi et al.16 have demonstrated patterns corresponding to orthopoxvirus histopathologic features, which was confirmed to be cowpox virus in a child. This tool can guide to a viral infection and a correct diagnosis. In conclusion, our clinicopathologic observations highlight mpxv cutaneous infection with simultaneous herpes simplex virus and cytomegalovirus coinfections in the same skin lesions. In this era of multiple coexisting ongoing and newly emerging viral pandemics, unusual cutaneous manifestations with atypical modes of transmission warrant high vigilance by clinicians and pathologists to consider emerging viral zoonotic outbreaks with modified modes of transmission and consider multiple viral coinfections, particularly in certain vulnerable social groups. Badr AbdullGaffar carried out conceptualization, histologic data collection, and data analysis and wrote and edited the manuscript. Suad Abdulrahman carried out clinical data collection and analysis, and reviewed, and approved the final manuscript draft. The authors declare no conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Monkeypox
Concomitant
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Infectious bursal disease
Newcastle Disease
Recombinant virus
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Recombinant virus
Poxviridae
Duck embryo vaccine
Attenuated vaccine
Orthopoxvirus
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ABSTRACT Since the development of a system for generating vesicular stomatitis virus (VSV) from plasmid DNAs, our laboratory has reported the expression of several different glycoproteins from recombinant VSVs. In one of these studies, high-level expression of an influenza virus hemagglutinin (HA) from a recombinant VSV-HA and efficient incorporation of the HA protein into the virions was reported (E. Kretzschmar, L. Buonocore, M. J. Schnell, and J. K. Rose, J. Virol. 71:5982–5989, 1997). We report here that VSV-HA is an effective intranasal vaccine vector that raises high levels of neutralizing antibody to influenza virus and completely protects mice from bronchial pneumonia caused by challenge with a lethal dose of influenza A virus. Additionally, these recombinant VSVs are less pathogenic than wild-type VSV (serotype Indiana). This vector-associated pathogenicity was subsequently eliminated through introduction of specific attenuating deletions. These live attenuated recombinant VSVs have great potential as vaccine vectors.
Recombinant virus
Mononegavirales
Vesicular Stomatitis
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