Orthopoxvirus

What is Orthopoxvirus?

Orthopoxviruses (OPXVs) belong to a group of nucleoplasmic large DNA viruses. Human pathogenic OPXV (hpOPXV) includes at least 5 viruses. Among them, smallpox virus and monkeypox virus are the most dangerous viral pathogens, which are a class of human infectious pathogens. Other hpOPXVs with low toxicity include vaccinia virus, vaccinia virus, and camelpox virus. Although smallpox was eradicated globally in the 80s of the 20th century, it remains one of the top targets of bioterrorism in countries around the world, given its potential to leak from laboratories to the outside world or be weaponized by terrorists. Monkeypox used to be confined to the African continent. However, since the beginning of May 2022, monkeypox outbreaks have been reported simultaneously in more than 100 different regions, which has led the World Health Organization to declare the current round of monkeypox outbreak a public health emergency of international concern.

Orthopoxvirus family

Orthopoxviruses are a family of double-stranded DNA viruses that belong to the nucleoplasmic region of eukaryotic cells and are infected with complex double-layer lipid envelopes and brick-shaped or ovoid virions. Orthopoxviruses are known for their large genome (about 130-300 kb) and their ability to code for more than 200 proteins. The family includes a variety of pathogens, such as smallpox virus, Vaccinia virus, and monkeypox virus. These viruses can cause serious diseases in mammals, including humans. Orthopoxviruses are mainly transmitted through contact infection, with smallpox virus causing large-scale global epidemics.

Orthopoxvirus structure

Poxviridae is the most structurally complex group of viruses known to date, with oval or brick-like poxvirions with a length of about 200-400 nm and an axial ratio of 1.2-1.7. The membrane is a typical 50-55 nm lipoprotein bilayer, wrapped around the core, and the outer surface is covered with randomly arranged tubular elements (STEs), with an average width of 7 nm and a length of 100 nm, and the virions are composed of nuclei and related side bodies surrounded by the membrane, which are sufficiently infectious. However, for infection with certain strains of viruses and certain cells, virions acquire an additional lipid bilayer that has its own unique chemical composition called envelope. This envelope contains about twice as many phospholipids as unenveloped virions, and numerous studies have shown that antigens on the viral envelope can induce immunity and protect Sufeng against poxviruses. The poxvirus envelope contains at least 7 different glycoproteins, as well as a major non-glycosylated acylated peptide.

Fig.1 Structure of the double-coated orthopoxvirus. (Ivanov Daniel Toshkov, et al., 2023)

Orthopoxvirus genome

The orthopoxvirus genome is a linear double-stranded DNA with inverse tandem repeats of variable length at both ends, forming a hairpin structure. According to the complete sequencing information of Copenhagen and WR virus strains, the genome of vaccinia virus is 191 kbp in length, and the reverse terminal repeat (ITR) of 12 kbp is not terminated by a covalently linked single-stranded hairpin loop, and the sequence is rich in AT, containing short direct repeats and multiple ORFs. Orthopoxvirus replicate completely in the cytoplasm and are less dependent on the DNA and RNA of the host cell. Viruses can synthesize new genes by generating and breaking down large tandem molecules, and the packaging of new genes is not strict, which provides favorable conditions for genome amplification, and in the process, viruses acquire new functions to complete evolution.

Fig.2 Scheme of orthopoxvirus genome. (Babkin Igor V., 2015)

Orthopoxvirus disease

Orthopoxvirus is a group of viruses that cause serious infectious diseases, the most famous of which is the Variola virus, which caused the deadly smallpox disease in human history. Smallpox was eradicated in the 20th century through global vaccination, but other members of the genus orthopoxvirus, such as Cowpox virus and Monkeypox virus, still cause infection in humans. These viruses can be transmitted through direct contact, aerosols, or animal bites, causing symptoms such as fever, rash, and general malaise. Although vaccination has been effective in controlling some of the diseases caused by orthopoxviruses, emerging viruses such as monkeypox still need attention and research to prevent potential outbreaks.

Orthopoxvirus testing

Assays for orthopoxvirus include PCR testing, serology testing, and viral culture. PCR testing is a highly sensitive and specific molecular diagnostic method that determines the presence of virus by amplifying viral DNA. Serologic tests confirm previous infection with orthopoxvirus by detecting antibodies, such as ELISA and IFA (indirect immunofluorescence). Viral culture, on the other hand, involves culturing the virus in a sample in a laboratory, and although this is a highly accurate method, it is usually reserved for specific laboratories due to the need for facilities with a high biosafety level. These methods are widely used in clinical diagnosis, epidemiological investigation, and research work.

Orthopoxvirus treatment

Vaccine therapy

Currently, there is no particularly effective treatment for rthopoxvirus infection, which relies mainly on supportive care. Isolation and tracing of sick people, sick animals and contacts is an important means of preventing the spread of the virus. Typically, quarantine is required for 6 weeks from the date of exposure. In addition, the smallpox vaccine is up to 85% effective as a preventive measure. The United States Centers for Disease Control and Prevention recommends that smallpox vaccination should be given within 2 weeks of exposure, with 4 days being most effective, in the absence of a history of protective contact with a confirmed patient or sick animal.

Medicine therapy

In terms of pharmacological treatment, current antiviral options include Tecovirimat (ST-246), Cyclic-HPMPC, and Cidofovir (CDV), which play an important role in controlling orthopoxvirus outbreaks.

Tecovirimat (ST-246): Tecovirimat is an antiviral drug developed by a high-throughput screening method that binds to the viral F13L protein and blocks the release of the virus from target cells, thereby blocking viral transmission. The drug has shown good anti-poxvirus activity in a variety of cell lines and has shown high safety and efficacy in clinical trials and animal models. In 2018, Tecovirimat was approved for the treatment of smallpox virus infection.

Cyclic HPMPC: A potent antiviral drug that has shown remarkable efficacy in multiple viral infection models. The study showed that cyclic HPMPC was able to increase arterial oxygen saturation levels in mice infected with the deadly vaccinia virus (IHD strain), indicating its therapeutic effect on severe viral infections. In addition, in studies of congenital guinea pig cytomegalovirus (GPCMV) infection, circular HPMPC significantly improved infection outcomes and effectively reduced viral replication in guinea pig models. These findings suggest that cyclic hmpc has a wide range of potential applications in antiviral therapy, especially in response to highly pathogenic viral infections.

Cidofovir (CDV): Cidofovir was developed by Gilead in United States and was originally used to treat AIDS-associated cytomegalovirus (CMV) retinitis. It exerts an antiviral effect by interfering with viral DNA synthesis by inhibiting viral DNA polymerase. However, because the drug is excreted through the kidneys, it may trigger dose-dependent nephrotoxicity, limiting its use.

Despite advances in the treatment of orthopoxviruses with nucleoside antivirals, mutations in viral DNA polymerase may raise resistance issues. Therefore, it is still necessary to continue to develop new drugs with different mechanisms of action to effectively respond to possible outbreaks. In addition, in tissue cultures, some compounds have shown efficacy against orthopoxvirus infection, such as Mitoxantrone, Tetrapyrrole, and Demycin. Brincidofovir and Tecovirimat have been approved for the treatment of smallpox and monkeypox, respectively. In addition, interferons and their inducers, as well as various nucleosides or nucleotides, have also shown activity against orthopoxvirus.

References

• Ivanov, Daniel Toshkov, et al., Antivirals for the treatment of Monkeypox: utilization in the general and HIV-positive population and gaps for research. A short narrative review. Le Infezioni in Medicina 31.2 (2023): 186.
• Babkin, Igor V., and Irina N. Babkina. The origin of the variola virus. Viruses 7.3 (2015): 1100-1112.

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