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Antimicrobial Agents and Chemotherapy Dec 2022Tecovirimat is an antiviral drug initially developed against variola virus (VARV) to treat smallpox infection. Due to its mechanism of action, it has activity against... (Review)
Review
Tecovirimat is an antiviral drug initially developed against variola virus (VARV) to treat smallpox infection. Due to its mechanism of action, it has activity against the family of orthopoxviruses, including vaccinia and the human monkeypox virus (HMPXV). Efficacy studies have thus far been limited to animal models, with human safety trials showing no serious adverse events. Currently approved by the FDA only for the treatment of smallpox, tecovirimat shows promise for the treatment of HMPXV. Tecovirimat has been prescribed via an expanded access for an investigational new drug protocol during the 2022 outbreak. This review will examine the literature surrounding tecovirimat's mechanism of action, pharmacokinetics, safety, efficacy, and potential for resistance.
Topics: Animals; Humans; Smallpox; Monkeypox virus; Variola virus; Antiviral Agents; Benzamides; Isoindoles; Mpox (monkeypox)
PubMed: 36374026
DOI: 10.1128/aac.01226-22 -
Viruses Mar 2023Mpox, formerly called monkeypox, is now the most serious orthopoxvirus (OPXV) infection in humans. This zoonotic disease has been gradually re-emerging in humans with an... (Review)
Review
Mpox, formerly called monkeypox, is now the most serious orthopoxvirus (OPXV) infection in humans. This zoonotic disease has been gradually re-emerging in humans with an increasing frequency of cases found in endemic areas, as well as an escalating frequency and size of epidemics outside of endemic areas in Africa. Currently, the largest known mpox epidemic is spreading throughout the world, with over 85,650 cases to date, mostly in Europe and North America. These increased endemic cases and epidemics are likely driven primarily by decreasing global immunity to OPXVs, along with other possible causes. The current unprecedented global outbreak of mpox has demonstrated higher numbers of human cases and greater human-to-human transmission than previously documented, necessitating an urgent need to better understand this disease in humans and animals. Monkeypox virus (MPXV) infections in animals, both naturally occurring and experimental, have provided critical information about the routes of transmission; the viral pathogenicity factors; the methods of control, such as vaccination and antivirals; the disease ecology in reservoir host species; and the conservation impacts on wildlife species. This review briefly described the epidemiology and transmission of MPXV between animals and humans and summarizes past studies on the ecology of MPXV in wild animals and experimental studies in captive animal models, with a focus on how animal infections have informed knowledge concerning various aspects of this pathogen. Knowledge gaps were highlighted in areas where future research, both in captive and free-ranging animals, could inform efforts to understand and control this disease in both humans and animals.
Topics: Animals; Humans; Monkeypox virus; Animals, Wild; Mpox (monkeypox); Zoonoses; Poxviridae Infections; Models, Animal
PubMed: 37112885
DOI: 10.3390/v15040905 -
Antiviral Chemistry & Chemotherapy 2008Surrogate animal models must be used for testing antiviral agents against variola (smallpox) virus infections. Once developed, these, compounds can be stockpiled for use... (Review)
Review
Surrogate animal models must be used for testing antiviral agents against variola (smallpox) virus infections. Once developed, these, compounds can be stockpiled for use in the event of a bioterrorist incident involving either variola or monkeypox virus, or used to treat an occasional serious orthopoxvirus infection, such as disseminated vaccinia complication following exposure to the live virus vaccine. Recently, considerable progress has been made in the discovery of novel antiviral agents found active against orthopoxviruses in vivo. This includes the development of new animal models or refinement of existing ones for compound efficacy testing. Current mouse models employ ectromelia, cowpox and vaccinia (WR and IHD strains) viruses with respiratory (lung) or tail lesion infections commonly studied. Rabbitpox and vaccinia (WR strain) viruses are available for rabbit infections. Monkeypox and variola viruses are used for infecting monkeys. This review describes these and other animal models, and covers compounds found active in vivo from 2003 to date. Cidofovir, known to be active against orthopox virus infections prior to 2003, has been studied extensively over recent years. New compounds showing promise are orally active inhibitors of orthopoxvirus infections that include ether lipid prodrugs of cidofovir and (S)-HPMPA, ST-246, N-methanocarbathymidine (N-MCT) and SRI 21950 (a 4'-thio derivative of iododeoxyuridine). Another compound with high activity but requiring parenteral administration is HPMPO-DAPy. Further development of these compounds is warranted.
Topics: Adenine; Animals; Antiviral Agents; Benzamides; Cidofovir; Cytosine; Disease Models, Animal; Drug Discovery; Humans; Isoindoles; Organophosphonates; Orthopoxvirus; Prodrugs
PubMed: 19024628
DOI: 10.1177/095632020801900302 -
Emerging Infectious Diseases Oct 2021Cowpox virus (CPXV) has an animal reservoir and is typically transmitted to humans by contact with infected animals. In 2017, CPXV infection of a pregnant woman in...
Cowpox virus (CPXV) has an animal reservoir and is typically transmitted to humans by contact with infected animals. In 2017, CPXV infection of a pregnant woman in France led to the death of her fetus. Fetal death after maternal orthopoxvirus (smallpox) vaccination has been reported; however, this patient had not been vaccinated. Investigation of the patient's domestic animals failed to demonstrate prevalence of CPXV infection among them. The patient's diagnosis was confirmed by identifying CPXV DNA in all fetal and maternal biopsy samples and infectious CPXV in biopsy but not plasma samples. This case of fetal death highlights the risk for complications of orthopoxvirus infection during pregnancy. Among orthopoxviruses, fetal infection has been reported for variola virus and vaccinia virus; our findings suggest that CPXV poses the same threats for infection complications as vaccinia virus.
Topics: Animals; Cowpox; Cowpox virus; Female; Fetal Death; Fetus; France; Humans; Orthopoxvirus; Young Adult
PubMed: 34352194
DOI: 10.3201/eid2710.204818 -
The Lancet. Infectious Diseases May 2023WHO has declared human mpox (formerly known as monkeypox) a global public health emergency since July, 2022. When case numbers were increasing, so did clinicians'... (Review)
Review
WHO has declared human mpox (formerly known as monkeypox) a global public health emergency since July, 2022. When case numbers were increasing, so did clinicians' exposures to new elements of the disease. Additionally, the burden of mpox is particularly apparent in immunocompromised patients, who can have more variable and severe manifestations of disease across organ systems. In this Grand Round, we report novel and severe oculocutaneous manifestations of mpox in this population, which are both sight and life threatening. Specifically, we highlight two patients with mpox and AIDS who had refractory skin necrosis that progressed to either ocular compromise or panfacial gangrene, or both. Both patients ultimately died due to systemic complications of their infections. Through clinical analogies, we show how past experiences with related orthopoxviruses, such as variola virus (smallpox) and vaccinia virus, can add useful context for understanding and treating these new disease states. We suspect that in patients who are immunocompromised, monkeypox virus can clinically evolve not only via viraemia but also through direct intradermal spread. We propose that intradermal spread occurs by a process clinically and immunologically analogous to progressive vaccinia, a complication previously seen after conventional smallpox vaccination. We share evidence in support of this theory and implications regarding early management and post-exposure prophylaxis for at-risk populations. Content note: this Grand Round contains graphic images of mpox lesions of the eyes and face.
Topics: Humans; Monkeypox virus; Mpox (monkeypox); Smallpox; Vaccinia virus; Viremia
PubMed: 36702137
DOI: 10.1016/S1473-3099(22)00869-6 -
Viruses May 2017Traditionally, virus taxonomy relied on phenotypic properties; however, a sequence-based virus taxonomy has become essential since the recent requirement of a species to...
Traditionally, virus taxonomy relied on phenotypic properties; however, a sequence-based virus taxonomy has become essential since the recent requirement of a species to exhibit monophyly. The species has failed to meet this requirement, necessitating a reexamination of this species. Here, we report the genomic sequences of nine and, by combining them with the available data of 37 additional genomes, confirm polyphyly of and find statistical support based on genetic data for more than a dozen species. These results are discussed in light of the current International Committee on Taxonomy of Viruses species definition, as well as immediate and future implications for poxvirus taxonomic classification schemes. Data support the recognition of five monophyletic clades of as valid species.
Topics: Animals; Cell Line; Cowpox virus; Genome, Viral; Genomics; Phylogeny; Poxviridae; Vaccinia virus
PubMed: 28486428
DOI: 10.3390/v9050101 -
Viruses Aug 2017Taterapox virus (TATV), which was isolated from an African gerbil () in 1975, is the most closely related virus to variola; however, only the original report has...
Taterapox virus (TATV), which was isolated from an African gerbil () in 1975, is the most closely related virus to variola; however, only the original report has examined its virology. We have evaluated the tropism of TATV in vivo in small animals. We found that TATV does not infect , a species of African dormouse, but does induce seroconversion in the Mongolian gerbil () and in mice; however, in wild-type mice and gerbils, the virus produces an unapparent infection. Following intranasal and footpad inoculations with 1 × 10⁶ plaque forming units (PFU) of TATV, immunocompromised mice showed signs of disease but did not die; however, SCID mice were susceptible to intranasal and footpad infections with 100% mortality observed by Day 35 and Day 54, respectively. We show that death is unlikely to be a result of the virus mutating to have increased virulence and that SCID mice are capable of transmitting TATV to C57BL/6 and C57BL/6 animals; however, transmission did not occur from TATV inoculated wild-type or mice. Comparisons with ectromelia (the etiological agent of mousepox) suggest that TATV behaves differently both at the site of inoculation and in the immune response that it triggers.
Topics: Animals; Antiviral Agents; Disease Models, Animal; Ectromelia virus; Ectromelia, Infectious; Host Specificity; Mice; Mice, Inbred C57BL; Mice, SCID; Orthopoxvirus; Poxviridae Infections; STAT1 Transcription Factor; Viral Tropism
PubMed: 28763036
DOI: 10.3390/v9080203 -
Cell Reports Jan 2024Investigating immune memory to vaccinia virus and pre-existing immunity to mpox virus (MPXV) among the population is crucial for the global response to this ongoing mpox...
Investigating immune memory to vaccinia virus and pre-existing immunity to mpox virus (MPXV) among the population is crucial for the global response to this ongoing mpox epidemic. Blood was sampled from vaccinees inoculated with vaccinia virus Tiantan (VTT) strain born before 1981 and unvaccinated control subjects born since 1982. After at least 40 years of the inoculation, 60% or 5% VTT vaccinees possess neutralizing antibodies (NAbs) to VTT or MPXV, with at least 50% having T cell memory to VTT protein antigens. Notably, 46.7% vaccinees show pre-existing T cell responses to MPXV. Broad pre-existing CD8 T cell reactivities to MPXV are detected not only against conserved epitopes but also against variant epitopes between VTT and MPXV. Persistent NAbs and T cell memory to VTT among vaccinees, along with pre-existing T cells to MPXV among both vaccinees and the unvaccinated population, indicate a particular immune barrier to mpox.
Topics: Humans; Vaccinia virus; Monkeypox virus; Mpox (monkeypox); Immunity, Cellular; Antibodies, Neutralizing; China; Epitopes; Immunity, Humoral
PubMed: 38159277
DOI: 10.1016/j.celrep.2023.113609 -
The Tohoku Journal of Experimental... Nov 2022Human Monkeypox (HMPX) outbreak in the year 2022 occurs in many countries outside of the African regions, a common location of such outbreaks, with a considerable rate... (Review)
Review
Human Monkeypox (HMPX) outbreak in the year 2022 occurs in many countries outside of the African regions, a common location of such outbreaks, with a considerable rate of human-to-human transmission, which was an uncommon route of infection before. The epidemiological reports also represent a sharping pace of infection spreading between communities rather than in previous outbreaks as the following pace of afflictions is unpredictable. Also, the cautions regarding the sexually transmitted infection of the such virus have been raised in this outbreak. Further, the main reservoirs of the recent outbreaks are yet to be revealed. As a consequence, the World Health Organization (WHO) has declared the 2022 HMPX outbreak as an "Atypical" phenomenon compared to its previous characteristics. To better recognize the properties of this outbreak, herein we systematically described and compared the historical evidence of monkeypox virus outbreaks in the aspects of epidemiological, clinical, and molecular evolutions since its emergence, as well as an explanation of the previous investigations and considerations of WHO and other international health societies over time. The history of human and monkeypox virus interaction during the past 64 years provides viewpoints on preventing strategies and assessing the present and potential future hazards of health implications.
Topics: Humans; Mpox (monkeypox); Monkeypox virus; Disease Outbreaks
PubMed: 36198504
DOI: 10.1620/tjem.2022.J081 -
Virology Nov 2012Vaccinia virus (VACV) enters cells by a low pH endosomal route or by direct fusion with the plasma membrane. We previously found differences in entry properties of...
Vaccinia virus (VACV) enters cells by a low pH endosomal route or by direct fusion with the plasma membrane. We previously found differences in entry properties of several VACV strains: entry of WR was enhanced by low pH, reduced by bafilomycin A1 and relatively unaffected by heparin, whereas entry of IHD-J, Copenhagen and Elstree were oppositely affected. Since binding and entry modes may have been selected by specific conditions of in vitro propagation, we now examined the properties of three distinct, recently isolated cowpox viruses and a monkeypox virus as well as additional VACV and cowpox virus strains. The recent isolates were more similar to WR than to other VACV strains, underscoring the biological importance of endosomal entry by orthopoxviruses. Sequence comparisons, gene deletions and gene swapping experiments indicated that viral determinants, other than or in addition to the A26 and A25 "fusion-suppressor" proteins, impact entry properties.
Topics: Animals; Cell Line; Chlorocebus aethiops; Cowpox virus; Endosomes; Glycosaminoglycans; HeLa Cells; Heparin; Humans; Hydrogen-Ion Concentration; Macrolides; Monkeypox virus; Open Reading Frames; Orthopoxvirus; Species Specificity; Vaccinia virus; Virus Internalization
PubMed: 22999097
DOI: 10.1016/j.virol.2012.08.044