Virology of the human monkeypox virus


The first case of human monkeypox virus (hMPXV) was confirmed by the United Kingdom Health Security Agency (UKHSA) in a person returning from Nigeria on 7 May 2022. This patient developed skin rashes a few days before his trip to the UK during a hospital stay that took place on his arrival in the UK. hMPXV was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) using a vesicular swab specimen. After that, more than 1,500 cases were suspected or confirmed in 45 countries, prompting the World Health Organization (WHO) to call an emergency meeting to curb the rapid spread of the virus.

MPXV is a double-stranded DNA virus belonging to the genus Orthopoxvirus and the family Poxviridae. It is a zoonotic virus that is on the WHO list of viruses with pandemic or epidemic potential. It is a 200-250 nm, enveloped, cytoplasmic virus that can enter the host cell by binding to glycosaminoglycans. However, only limited studies are available on the origin of hMPXV, pathogenesis, and treatment.

A new review in the virus research The journal aims to provide an overview of recent advances that have been reported in relation to hMPXV virology.

Review: The virology of human monkeypox virus (hMPXV): A brief overview.  Image credit: Spotted Yeti/ShutterstockReview: The virology of human monkeypox virus (hMPXV): A brief overview. Image credit: Spotted Yeti/Shutterstock

origin of the virus

The virus was first isolated from smallpox-like vesiculopustular lesions found in imported monkeys in Denmark. Over the next few years, similar outbreaks in monkeys were observed elsewhere. A widespread outbreak took place at a zoo in Rotterdam in 1966. The virus was thought to first affect South American giant anteaters before spreading to various great apes and monkeys. First human infections were detected in individuals from Liberia and the Democratic Republic of the Congo in 1970, confirming hMPXV as a distinct virus.

After that, the virus was found to be endemic in west and central African counties from 1970 to 2003. The first report of an outbreak outside of Africa was reported in the United States during imports of nine different species of mammals from Ghana in 2003. A spill-over event was identified when a 3-year-old girl was taken to the emergency room after being bitten by a prairie dog. After that, sporadic outbreaks were observed worldwide, which can be traced back to the endemic areas of Africa. However, exact evidence of its natural reservoir is still under investigation.

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MPXV clades

Orthopoxvirus is genetically and antigenically similar and comprises open reading frames (ORFs) with greater than 90% sequence similarity among its members. Evolutionary changes in the virus are reported to be due to gene loss at the terminal ends of the genome and variations in gene copy numbers. The hMPXV genome is approximately 197 kb in size and comprises approximately 190 non-overlapping ORFs along with a central coding region sequence (CRS) whose ends are flanked by inverted terminal repeats (ITRs).

The most commonly described hMPXV clades are the West African (WA) and Central African/Congo Basin (CA) clades. The WA clade has been found to cause milder infections with lower mortality rates, while the CA clade causes more severe infections with a 10% mortality in unvaccinated individuals. Previous studies have shown that the CA clade contains 173 unique functional genes, while the WA clade contains 171. In addition, 53 of the 56 virulence genes were observed in both clades. The virulence difference between both clades was observed due to differences in the COP-C3L, BR-209 and BR-203 gene orthologs. In addition, the D14R gene was found to be another key anti-inflammatory factor that was absent in the WA clade and also contributed to the difference in virulence.

A recent analysis of the hMPXV genome from the 2022 outbreak revealed cytosine (C) to thymine (T) and guanine (G) to adenine (A) base mutations that could be caused by the enzyme APOBEC3. In addition, a 30 T-base long sequence was observed in the middle of the genome of the 2022 isolates, the role of which has yet to be determined.

pathogenesis

hMPXV pathogenesis involved virus entry, fusion, replication and release. Two infectious forms of the virus have been observed to be produced, intracellular mature virions (MV) and extracellular enveloped virions (EV). MVs are single-membrane bound while EVs comprise a distinct triple membrane. It has been found that antibodies and vaccines that are unable to attack and produce EV antigens offer less protection.

In addition, two multi-subunit complexes important for the completion of the viral infection cycle have been identified, the conserved oligomeric Golgi (COG) complex and the Golgi-associated retrograde protein (GARP) complex. The GARP complex supports retrograde endosomal transport and includes four vacuolar protein sorting genes (VPS). The COG complex helps maintain Golgi structure and intra-Golgi traffic regulation. It consists of two lobes, each composed of 4 associated subunits.

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Through bioinformatic analysis, the identification of two distinct regions, ORF 17 to 32 (R1) and ORF 179 to 193 (R2). Deleting one or both regions was found to reduce morbidity and mortality in mice, as well as attenuate viral replication. In addition, hMPXV was observed to upregulate core histones and downregulate histone expression regulatory factors and cell membrane ion channels associated with the host cell cycle.

Cytokine Storm

Similar to COVID-19, a cytokine storm was observed in hMPXV infection, resulting in high levels of interleukins IL-4, -5, -6 and -10 and low levels of tumor necrosis factor-alpha, interferon-alpha. and gamma, along with IL-2 and -12. hMPXV infections also induced a cascade of complementary B cell responses. In addition, six monoclonal antibodies were identified targeting A33, B5, L1, D8, H3 and A27, which protected against orthopoxviral respiratory and systemic infections.

Diagnostic modalities for hMPXV

Diagnosis of hMPXV can be made by viral culture and isolation, PCR, IgM/IgG serological testing, immunohistochemistry of specific antigens, and electron microscopy with negative staining of the rash. In addition, a sensitive diagnostic tool called Antibody Immuno Column for Analytical Processes (AICAP) immunofiltration tool was developed to detect all zoonotic orthopoxviruses. A recombinase polymerase amplification (RPA) assay has recently been developed that can detect the G2R gene of the virus in less than 7 minutes. Metabolic activity, along with lymph node size, can also determine the presence of hMPXV infection. Also includes positron emission tomography/computed tomography (PET/CT) imaging [18F]-Fluorodeoxyglucose (FDG) was found to accurately predict the course of hMPXV disease for non-human primate models.

treatment and prophylaxis

Antiviral treatment with cidofovir or another associated acyclic nucleoside phosphonate analogue was observed to be more effective in treating lethal hMPXV in monkeys after 24 hours of exposure compared to smallpox vaccination. However, a new antiviral called PAV-164 has been developed to inhibit MPXV replication and overcome resistance to available antivirals. Revesterol, a natural polyphenol, was also found to significantly reduce hMPXV replication in vitro against both classes.

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The Advisory Committee on Immunization Practices (ACIP) has recommended the use of the JYNNEOS vaccine as an alternative to the ACAM2000 vaccine in 2022. Developed from a replication-deficient modified vaccinia virus Ankara (MVA), JYNNEOS can be administered in a 2-dose schedule with 28 days between doses. Those exposed to more virulent orthopoxviruses are recommended to have a booster dose every two years, while those exposed to less virulent orthopoxviruses are recommended to have a booster dose every ten years.

Recently, a DNA vaccine known as 4pox was also developed to inhibit viral shedding and prevent the adverse effects of infection. In addition, recombinant vaccinia virus immunoglobulin (rVIG) and two human chimeric monoclonal antibodies, c8A and c7D11, were also found to be active against MPXV. In addition, CRISPR/Cas9-based targeted antivirals have also been observed to reduce the viral titer of orthopoxvirus by approximately 90%. With the advent of ring vaccination in countries such as the UK, US and Canada, it is critical to develop safer, more effective and more easily distributed vaccines that can reduce severity and prevent hMPXV infection.

The 2022 outbreak

The 2022 global eruption is interesting because it has no connections to West or Central Africa. Additionally, the transmission of the virus, mainly among men who have sex with men (MSM), is quite intriguing. The WA clade has been linked to the 2022 outbreak, which is known to cause mild infection and less human-to-human transmission. Increased human-animal interactions and climate change are thought to accelerate zoonotic spillover events. Epidemiological institutions and public health officials must be aware and vigilant to identify future zoonotic infections, provide treatment options, and guide the general population.

Conclusion

Human monkeypox virus is a neglected zoonotic pathogen that was discovered many years ago. However, the recent outbreak in 2022 underscores the need for constant surveillance of the virus and the development of new and effective therapies. In addition, more research needs to be done to manage and contain the rapid spread of hMPXV around the world.



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