-
Expert Opinion on Biological Therapy Apr 2012Poxviral vaccines have been given to over 1 billion people in the successful global eradication of smallpox. Recombinant poxviruses have been investigated extensively as... (Review)
Review
INTRODUCTION
Poxviral vaccines have been given to over 1 billion people in the successful global eradication of smallpox. Recombinant poxviruses have been investigated extensively as a novel immunotherapy for cancer, undergoing several iterations to optimize their immunogenicity and efficacy. The current platform expressing multiple costimulatory molecules plus a tumor-associated antigen such as PSA, that is, PSA-TRICOM (PROSTVAC-V/F), is promising and is currently in a Phase III randomized, placebo-controlled clinical trial in metastatic castration-resistant prostate cancer.
AREAS COVERED
This review discusses the clinical development of poxviral-based cancer vaccines, with a particular focus on the rationale for combining vaccines with other treatment modalities, including radiotherapy, chemotherapy, hormonal therapy, other immune-based therapies and molecularly targeted therapy. We also discuss the importance of appropriate patient selection in clinical trial design.
EXPERT OPINION
Preclinical and early clinical studies employing poxviral-vector vaccines have shown promising results with this novel immunologic approach, both alone and combined with other therapies. The challenges of translating the science of immunotherapy to clinical practice include clinical trial design that includes appropriate patient selection, appropriate end points and identification of meaningful surrogate biomarkers.
Topics: Animals; Cancer Vaccines; Genetic Vectors; Humans; Immunotherapy; Neoplasms; Poxviridae
PubMed: 22413824
DOI: 10.1517/14712598.2012.668516 -
Nature Communications Aug 2023The rapid spread of monkeypox in multiple countries has resulted in a global public health threat and has caused international concerns since May 2022. Poxvirus encoded...
The rapid spread of monkeypox in multiple countries has resulted in a global public health threat and has caused international concerns since May 2022. Poxvirus encoded M2 protein is a member of the poxvirus immune evasion family and plays roles in host immunomodulation via the regulation of innate immune response mediated by the NF-κB pathway and adaptive immune response mediated by B7 ligands. However, the interaction of monkeypox virus (MPXV) M2 with B7 ligands and structural insight into poxviral M2 function have remained elusive. Here we reveal that MPXV M2, co-existing as a hexamer and a heptamer, recognizes human B7.1 and B7.2 (hB7.1/2) with high avidities. The binding of oligomeric MPXV M2 interrupts the interactions of hB7.1/2 with CD28 and CTLA4 and subverts T cell activation mediated by B7.1/2 costimulatory signals. Cryo-EM structures of M2 in complex with hB7.1/2 show that M2 binds to the shallow concave face of hB7.1/2 and displays sterically competition with CD28 and CTLA4 for the binding to hB7.1/2. Our findings provide structural mechanisms of poxviral M2 function and immune evasion deployed by poxviruses.
Topics: Humans; Mpox (monkeypox); Monkeypox virus; CTLA-4 Antigen; CD28 Antigens; Ligands; Poxviridae; T-Lymphocytes
PubMed: 37626059
DOI: 10.1038/s41467-023-40748-2 -
Viruses May 2012For many viruses, one or two proteins enable cell binding, membrane fusion and entry. The large number of proteins employed by poxviruses is unprecedented and may be... (Review)
Review
For many viruses, one or two proteins enable cell binding, membrane fusion and entry. The large number of proteins employed by poxviruses is unprecedented and may be related to their ability to infect a wide range of cells. There are two main infectious forms of vaccinia virus, the prototype poxvirus: the mature virion (MV), which has a single membrane, and the extracellular enveloped virion (EV), which has an additional outer membrane that is disrupted prior to fusion. Four viral proteins associated with the MV membrane facilitate attachment by binding to glycosaminoglycans or laminin on the cell surface, whereas EV attachment proteins have not yet been identified. Entry can occur at the plasma membrane or in acidified endosomes following macropinocytosis and involves actin dynamics and cell signaling. Regardless of the pathway or whether the MV or EV mediates infection, fusion is dependent on 11 to 12 non-glycosylated, transmembrane proteins ranging in size from 4- to 43-kDa that are associated in a complex. These proteins are conserved in poxviruses making it likely that a common entry mechanism exists. Biochemical studies support a two-step process in which lipid mixing of viral and cellular membranes is followed by pore expansion and core penetration.
Topics: Conserved Sequence; Poxviridae; Viral Proteins; Virion; Virus Internalization
PubMed: 22754644
DOI: 10.3390/v4050688 -
Emerging Infectious Diseases Feb 2023To investigate animal reservoirs of monkeypox virus in Nigeria, we sampled 240 rodents during 2018-2019. Molecular (real-time PCR) and serologic (IgM) evidence indicated...
To investigate animal reservoirs of monkeypox virus in Nigeria, we sampled 240 rodents during 2018-2019. Molecular (real-time PCR) and serologic (IgM) evidence indicated orthopoxvirus infections, but presence of monkeypox virus was not confirmed. These results can be used to develop public health interventions to reduce human infection with orthopoxviruses.
Topics: Animals; Humans; Mpox (monkeypox); Rodentia; Nigeria; Poxviridae Infections; Monkeypox virus; Orthopoxvirus
PubMed: 36692495
DOI: 10.3201/eid2902.221411 -
Immunological Reviews Jan 2011The eradication of smallpox, one of the great triumphs of medicine, was accomplished through the prophylactic administration of live vaccinia virus, a comparatively... (Review)
Review
The eradication of smallpox, one of the great triumphs of medicine, was accomplished through the prophylactic administration of live vaccinia virus, a comparatively benign relative of variola virus, the causative agent of smallpox. Nevertheless, recent fears that variola virus may be used as a biological weapon together with the present susceptibility of unimmunized populations have spurred the development of new-generation vaccines that are safer than the original and can be produced by modern methods. Predicting the efficacy of such vaccines in the absence of human smallpox, however, depends on understanding the correlates of protection. This review outlines the biology of poxviruses with particular relevance to vaccine development, describes protein targets of humoral and cellular immunity, compares animal models of orthopoxvirus disease with human smallpox, and considers the status of second- and third-generation smallpox vaccines.
Topics: Animals; Antibodies, Viral; Biological Warfare Agents; Disease Models, Animal; Gene Expression Regulation, Viral; Humans; Mice; Orthopoxvirus; Poxviridae Infections; Smallpox; Smallpox Vaccine; Vaccines; Vaccinia virus; Variola virus
PubMed: 21198662
DOI: 10.1111/j.1600-065X.2010.00975.x -
Viruses Dec 2020The global emergence of zoonotic viruses, including poxviruses, poses one of the greatest threats to human and animal health. Forty years after the eradication of... (Review)
Review
The global emergence of zoonotic viruses, including poxviruses, poses one of the greatest threats to human and animal health. Forty years after the eradication of smallpox, emerging zoonotic orthopoxviruses, such as monkeypox, cowpox, and vaccinia viruses continue to infect humans as well as wild and domestic animals. Currently, the geographical distribution of poxviruses in a broad range of hosts worldwide raises concerns regarding the possibility of outbreaks or viral dissemination to new geographical regions. Here, we review the global host ranges and current epidemiological understanding of zoonotic orthopoxviruses while focusing on orthopoxviruses with epidemic potential, including monkeypox, cowpox, and vaccinia viruses.
Topics: Animals; Geography, Medical; Host Specificity; Humans; Orthopoxvirus; Poxviridae Infections; Viral Zoonoses
PubMed: 33396609
DOI: 10.3390/v13010043 -
Microbiology and Molecular Biology... Dec 2009Studies of the functional proteins encoded by the poxvirus genome provide information about the composition of the virus as well as individual virus-virus protein and... (Review)
Review
Studies of the functional proteins encoded by the poxvirus genome provide information about the composition of the virus as well as individual virus-virus protein and virus-host protein interactions, which provides insight into viral pathogenesis and drug discovery. Widely used proteomic techniques to identify and characterize specific protein-protein interactions include yeast two-hybrid studies and coimmunoprecipitations. Recently, various mass spectrometry techniques have been employed to identify viral protein components of larger complexes. These methods, combined with structural studies, can provide new information about the putative functions of viral proteins as well as insights into virus-host interaction dynamics. For viral proteins of unknown function, identification of either viral or host binding partners provides clues about their putative function. In this review, we discuss poxvirus proteomics, including the use of proteomic methodologies to identify viral components and virus-host protein interactions. High-throughput global protein expression studies using protein chip technology as well as new methods for validating putative protein-protein interactions are also discussed.
Topics: Animals; Genome, Viral; Host-Pathogen Interactions; Humans; Poxviridae; Poxviridae Infections; Proteomics; Two-Hybrid System Techniques; Viral Proteins; Virion
PubMed: 19946139
DOI: 10.1128/MMBR.00026-09 -
Current Opinion in Virology Dec 2012Host range factors, expressed by the poxvirus family, determine the host tropism of species, tissue, and cell specificity. C7L family members exist in the genomes of... (Review)
Review
Host range factors, expressed by the poxvirus family, determine the host tropism of species, tissue, and cell specificity. C7L family members exist in the genomes of most sequenced mammalian poxviruses, suggesting an evolutionarily conserved effort adapting to the hosts. In general, C7L orthologs influence the host tropism in mammalian cell culture, and for some poxviruses it is essential for the complete viral life cycle in vitro and in vivo. The C7L family members lack obvious sequence homology with any other known viral or cellular proteins. Here we review recent findings from an evolutionary perspective and summarize recent progress that broadens our view on the role of C7L family members in mediating poxvirus host range and antagonizing the host defense system.
Topics: Adaptation, Biological; Animals; Evolution, Molecular; Host Specificity; Humans; Mammals; Poxviridae; Viral Proteins; Viral Tropism
PubMed: 23103013
DOI: 10.1016/j.coviro.2012.09.012 -
Biomedical Journal Jun 2022Chemokines are small proteins that are critical for immune function, being primarily responsible for the activation and chemotaxis of leukocytes. As such, many viruses,... (Review)
Review
Chemokines are small proteins that are critical for immune function, being primarily responsible for the activation and chemotaxis of leukocytes. As such, many viruses, as well as parasitic arthropods, have evolved systems to counteract chemokine function in order to maintain virulence, such as binding chemokines, mimicking chemokines, or producing analogs of transmembrane chemokine receptors that strongly bind their targets. The focus of this review is the large group of chemokine binding proteins (CBP) with an emphasis on those produced by mammalian viruses. Because many chemokines mediate inflammation, these CBP could possibly be used pharmaceutically as anti-inflammatory agents. In this review, we summarize the structural properties of a diverse set of CBP and describe in detail the chemokine binding properties of the poxvirus-encoded CBP called vCCI (viral CC Chemokine Inhibitor). Finally, we describe the current and emerging capabilities of combining computational simulation, structural analysis, and biochemical/biophysical experimentation to understand, and possibly re-engineer, protein-protein interactions.
Topics: Animals; Carrier Proteins; Chemokines; Humans; Mammals; Poxviridae; Protein Binding; Viral Proteins
PubMed: 34311129
DOI: 10.1016/j.bj.2021.07.004 -
Bulletin of the World Health... 1980Increasing attention has been given to human monkeypox since the achievement of global smallpox eradication. Monkeypox, which was first described in Central Africa in...
Increasing attention has been given to human monkeypox since the achievement of global smallpox eradication. Monkeypox, which was first described in Central Africa in 1970, resembles smallpox clinically but differs from it epidemiologically. Forty-seven cases of human monkeypox have occurred since 1970 in 5 Central and West African countries; 38 of these cases have been reported from Zaire. The evolution of the illness and the sequelae of monkeypox and smallpox are the same; monkeypox has a case-fatality rate of about 17%. Children below 10 years of age comprise 83% of the cases. All cases have occurred in tropical rainforest areas and clustering of cases has been observed in certain zones within countries and within families. Person-to-person spread may have occurred in 4 cases; the secondary attack rate among susceptible, very close family members was 7.5% (3 cases/40 contacts) and among all susceptible contacts was 3.3% (4 cases/123 contacts)-much lower than the 25-40% secondary attack rate that occurs with smallpox. Although the low transmission rate and the low frequency of disease indicate that monkeypox is not a public health problem, more data are needed.Whilst many animals near human monkeypox cases have been demonstrated to have orthopoxvirus antibodies, the natural reservoir(s) and the vector(s) of monkeypox virus are unknown. Studies are in progress to identify the natural cycle of monkeypox virus and to define better the clinical and epidemiological features of this disease.
Topics: Adolescent; Adult; Africa, Central; Child; Child, Preschool; Female; Humans; Infant; Male; Monkeypox virus; Population Surveillance; Poxviridae; Poxviridae Infections
PubMed: 6249508
DOI: No ID Found