Mutations in Monkeypox escape drugs and vaccines

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Monkeypox has infected more than 77,000 people in more than 100 countries worldwide, and – similar to COVID-19 – mutations have enabled the virus to grow stronger and smarter, evading antiviral drugs and vaccines in its mission to infect more people.

Now, a team of researchers at the University of Missouri have identified the specific mutations in the monkeypox virus that contribute to its continued infectiousness.

The findings could lead to several outcomes: modified versions of existing drugs used to treat people suffering from monkeypox or the development of new drugs that account for the current mutations to increase their effectiveness at reducing symptoms and the spread of the virus.

Kamlendra Singh, a professor in the MU College of Veterinary Medicine and Christopher S. Bond Life Sciences Center principal investigator, collaborated with Shrikesh Sachdev, Shree Lekha Kandasamy and Hickman High School student Saathvik Kannan, to analyze the DNA sequences of more 200 strains of monkeypox virus spanning multiple decades, from 1965, when the virus first started spreading, to outbreaks in the early 2000s and again in 2022.

“By doing a temporal analysis, we were able to see how the virus has evolved over time, and a key finding was the virus is now accumulating mutations specifically where drugs and antibodies from vaccines are supposed to bind,” Sachdev said. “So, the virus is getting smarter, it is able to avoid being targeted by drugs or antibodies from our body’s immune response and continue to spread to more people.”

Needles in a haystack

Singh has been studying virology and DNA genome replication for nearly 30 years. He said the homology, or structure, of the monkeypox virus is very similar to the vaccinia virus, which has been used as a vaccine to treat smallpox.

This enabled Singh and his collaborators to create an accurate, 3D computer model of the monkeypox virus proteins and identify both where the specific mutations are located and what their functions are in contributing to the virus becoming so infectious recently.

“Our focus is on looking at the specific genes involved in copying the virus genome, and monkeypox is a huge virus with approximately 200,000 DNA bases in the genome,” Singh said.

“The DNA genome for monkeypox is converted into nearly 200 proteins, so it comes with all the ‘armor’ it needs to replicate, divide and continue to infect others. Viruses will make billions of copies of itself and only the fittest will survive, as the mutations help them adapt and continue to spread.”

Kannan and Kandasamy examined five specific proteins while analyzing the monkeypox virus strains: DNA polymerase, DNA helicase, bridging protein A22R, DNA glycosylase and G9R.

“When they sent me the data, I saw that the mutations were occurring at critical points impacting DNA genome binding, as well as where drugs and vaccine-induced antibodies are supposed to bind,” Singh said.

“These factors are surely contributing to the virus’ increased infectivity. This work is important because the first step toward solving a problem is identifying where the problem is specifically occurring in the first place, and it is a team effort.”

The evolution of viruses

Researchers continue to question how the monkeypox virus has evolved over time. The efficacy of current CDC-approved drugs to treat monkeypox have been suboptimal, likely because they were originally developed to treat HIV and herpes but have since received emergency use authorization in an attempt to control the recent monkeypox outbreak.

“One hypothesis is when patients were being treated for HIV and herpes with these drugs, they may have also been infected with monkeypox without knowing, and the monkeypox virus got smarter and mutated to evade the drugs,” Singh said.

“Another hypothesis is the monkeypox virus may be hijacking proteins we have in our bodies and using them to become more infectious and pathogenic.”

Singh and Kannan have been collaborating since the COVID-19 pandemic began in 2020, identifying the specific mutations causing COVID-19 variants, including Delta and Omicron. Kannan was recently recognized by the United Nations for supporting their ‘Sustainable Development Goals,’ which help tackle the world’s greatest challenges.

“I could not have done this research without my team members, and our efforts have helped scientists and drug developers assist with these virus outbreaks, so it is rewarding to be a part of it,” Singh said.

“Mutations in the monkeypox virus replication complex: Potential contributing factors to the 2022 outbreak” was recently published in Journal of Autoimmunity. Co-authors on the study include Shrikesh Sachdev, Athreya Reddy, Shree Lekha Kandasamy, Siddappa Byrareddy, Saathvik Kannan and Christian Lorson.


Monkeypox viruses – classification and structure
Along with MPXV, the genus Orthopoxvirus comprises three more human-pathogen species: variola virus (VARV)– the causative agent of smallpox, vaccinia virus (VACV), and cowpox. VARV and MPXV often cause life-threatening diseases, while VACV and cowpox are usually associated with local lesions.

Out of two clades, the West African clade of MPXVs is characterized with less antigenic drift and virulence (38, 39). The Central African clade (clade 1) which is particularly endemic to the Congo Basin causes more severe symptoms of the disease as it is more virulent and transmissible (40, 41).

The MPXVs isolated since 2017 are categorized as a clade 3 which along with clade 2 belongs to the West African clade (41, 42). MPXVs identified during the 2017/2019 outbreaks belong to lineages A.1, A.2, and A1.1, while MPXVs isolated during the current multi-country outbreak belong to lineage B.1 (41, 43). Importantly, clade 3 is characterized by the high number of mutations allowing increasing the adaptability to humans (42).

MPXV like other poxviruses is a large (~280 nm X ~220 nm) (13), brick- or oval-shaped enveloped virus. The viral core is dumbbell-shaped and contains the enzymes necessary for uncoating and replication as well as the large ~197 kb long viral genome that is a linear dsDNA comprising over 190 open reading frames (ORFs) (3, 18).

The MPXV has a complex structure and its genome is not fully characterized. Although there are at least 90 essential ORFs, most of the ORFs still need to be identified and studied (3, 44) (Figure 2). Like other poxviruses, MPXV also has two forms–EEV and IMV. EEV has an additional outer membrane and is considered to play a major role in early dissemination while IMV is released during the cell lysis. Both forms induce the infection (45, 46).

FIGURE 2 The general structure of MPXV.

Infection, pathogenesis, and clinical manifestation
After MPXV transmission through contact with an infected animal, human, or contaminated objects, the virus enters the body, disseminates systematically via monocytic cells, and can infect most mammalian cells (47). According to the clinical studies, lymphoid tissues in the neck and throat represent the primary replication areas for MPXV. After the primary lymphatic dissemination of the virus, liver and spleen are the major targets for the infection. The spread of the virus into small dermal blood vessels gives rise to the skin infection and lesions (48).

The extracellular proteins of the poxviruses attach the glycans (laminin, heparin, and chondroitin sulfates) of host cells (49–51). H3L (heparan-binding surface IMV membrane protein), A29L (heparan-binding IMV surface membrane fusion protein), and E8L (chondroitin sulfate-binding IMV surface membrane adsorption protein) are among the proteins that are responsible for the attachment (49, 51). After the pH-dependent fusion and entry into the host cell, viral transcription takes place.

Notably, transcription occurs via the viral DNA-dependent RNA polymerase. Hence, unlike other DNA viruses, MPXV does not need to be transported into the nucleus, instead, with its own machinery, the transcription takes place in the cytoplasm. Following transcription, translation occurs on the ribosomes of the host cell (52, 53).

The majority of IMVs remain intracellularly and are released only upon the cell lysis while some of them become enveloped (intracellular enveloped virus (IEV)) by the additional outer membranes derived by the endoplasmic reticulum or Golgi apparatus. After the MPXV gains an additional membrane, it is either transported into the neighbor cell or outside the cell and becomes EEV (54). It is known that EEV infects the cells more efficiently compared with the IMV (55). Usually, the incubation period of MPXV lasts for approximately two weeks (56) and typically it is resolved within 2-4 weeks (22).

The MPX is characterized by similar symptoms as other poxviruses along with certain distinctive features. The common symptoms include fever, chills, body- and headaches, fatigue, sore throat, and rash that becomes papules and crust later while healing. Because of these similarities, MPX is often misdiagnosed with other poxviral diseases. The main difference between MPX and other poxvirus disease manifestations is that MPXV infection causes enlargement of lymph nodes before the development of rash (57–61). The rash is presented all over the body, usually concentrated on the face and extremities, however, the current multi-country outbreak of human MPX demonstrated the new tendency of atypical presentation.

During the 2022 MPXV outbreak the lesions are usually localized in the genitals and/or anus of the infected patients (3, 22–25) and patients experience extreme rectal pain and penile oedema (62, 63). The complications of the MPX disease may be even life-threatening, e.g., encephalitis, sepsis, etc. (22). Besides, MPXV can be vertically transmitted making pregnant women and fetus vulnerable (48).

Unfortunately, the lack of surveillance and health care in countries of Africa greatly contributes to the underdiagnoses of MPX and the spread of the virus, meaning that the numbers of daily cases have been more likely much higher than the officially recorded numbers (2). Notably, during the current outbreak, more MPX cases are detected in men who have sex with men (MSM) (62, 64–67). When the MPX cases were identified in Africa before spreading the virus outside the continent, it was notable that more confirmed cases were male. E.g., When 760 cases were detected in DRC during 2005-2007 through the surveillance program, the male patients (62.1%) predominated females (68).

Martinez et al. have revealed that in Spain, a region of Madrid, by June 2022, 508 MPX cases were identified out of which 99% were men. 84.1% of the total number of cases had condomless sexual intercourse with multiple partners before the onset of the MPX symptoms. 93% of them were men who had sex with men.

The distribution of the rash indicates that this type of close physical contact plays a major role in disease transmission (69). Remarkably, the tendency of smallpox vaccination among MSM is increasing (70). The illustration of MPX symptoms is given in Figure 3.

Figure 3

FIGURE 3 Pathogenesis and clinical manifestation of MPXV.

reference link : https://www.frontiersin.org/articles/10.3389/fimmu.2022.1050309/full


More information: Saathvik R. Kannan et al, Mutations in the monkeypox virus replication complex: Potential contributing factors to the 2022 outbreak, Journal of Autoimmunity (2022). DOI: 10.1016/j.jaut.2022.102928

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