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Monkeypox virus (MPXV) belongs to the Orthopoxvirus genus. Generally, viruses within the same genus share similar biological characteristics. The transmission mechanism of the monkeypox virus may be similar to that of the "poxvirus genus model virus"—vaccinia virus. The stages of virus maturation include four forms: intracellular mature virus (IMV), intracellular enveloped virus (IEV), cell-associated enveloped virus (CEV), and extracellular enveloped virus (EEV). Among these, IMV, CEV, and EEV are infectious. IMV is considered the virus particle responsible for transmission between hosts; EEV has a fragile membrane that cannot survive in the physical environment outside the host, and once it ruptures, it releases IMV particles that are fully infectious and relatively stable. CEV mainly facilitates intercellular transmission of the virus, while EEV is used for long-distance transmission. Some studies suggest that monkeypox CEV may remain on the cell surface and not be released as EEV.
（Note: The image is sourced from the Uniprot official website）
| Protein name | 14 kDa protein |
| Full length | 110 amino acids |
| Gene names | A29L |
| Accession | Q9YN60 |
| Species | Monkeypox virus |
A29L is a surface membrane protein of intracellular mature virus (IMV) and is homologous to A27 of the vaccinia virus (VACV). It is widely conserved in the poxvirus family. Research on vaccinia virus has found that the A27 protein plays multiple roles in the virus life cycle, such as binding to cell surface heparan sulfate, regulating membrane fusion, and mediating the transport of mature virus (IMV) to form enveloped virus (IEV).
A27 can bind to cell surface heparan sulfate and mediate cell fusion under low pH conditions in the nucleus. Additionally, A27 is involved in assembling the fusion inhibitor protein A26 in mature viruses (IMV). After MV is endocytosed by vesicles, the acidic environment within the endosome induces the dissociation of the A26 protein from MV, leading to the fusion of the viral membrane with the vesicle membrane. A27 interacts with the integral membrane protein A17, which then forms a protein complex with A26 through disulfide bonds, anchoring A26 to the mature virus (IMV) particles.
In addition to these functions, the A27 protein also promotes the release of enveloped viruses. A portion of the MV progeny in infected cells is transported from the viral factory to the Golgi network through an A27-dependent mechanism, acquiring a second membrane layer to become intracellular enveloped viruses (IEV). IEV is released through exocytosis.
M1R is homologous to the L1 protein of vaccinia virus and is a transmembrane protein found on the surface of mature IMV particles. It is encoded by the L1R ORF, is highly conserved, and plays an important role in virus particle assembly, virus entry, and maturation. L1 is essential for inducing cell-cell fusion triggered by low pH and is crucial for vaccinia virus replication. Co-immunoprecipitation experiments show that L1 interacts with A28 and some other components of the entry/fusion complex (EFC) and indirectly with F9, suggesting that L1 is an additional component of the viral entry machinery. L1-MV can attach to cells but cannot enter or induce membrane fusion. L1 physically interacts with the EFC and works in concert with other known entry proteins.
（Note: The image is sourced from the Uniprot official website）
| Protein name | M1R |
| Full length | 250 amino acids |
| Gene names | M1R |
| Accession | Q80KX3 |
| Species | Monkeypox virus |
A35R is a membrane component of intracellular enveloped virus particles (IEV) and extracellular enveloped virus particles (EEV), and it is homologous to the A33R protein of chordopoxviruses. Vaccinia virus spreads from one cell to another through both antibody-sensitive and antibody-resistant pathways, and the A33R protein plays a role in antibody-resistant transmission. Research has shown that the cytoplasmic domain of the A33R protein interacts with amino acids 91-111 of A36R, which directly participates in the formation of actin tails. The A33R protein is essential for the association of A36R protein with the IEV membrane. Additionally, the A33R binding site of A36R (amino acids 105-116) overlaps with the Nck binding site, a protein necessary for actin tail nucleation, suggesting that A33R may regulate viral particle movement and actin tail nucleation to prevent premature events.
（Note: The image is sourced from the Uniprot official website）
| Protein name | B6R |
| Full length | 317 amino acids |
| Gene names | B6R |
| Accession | Q773E2 |
| Species | Monkeypox virus |
B6R is a host range protein located on the membrane of extracellular enveloped virus particles (EEV) and is homologous to the complement control protein B5 of vaccinia virus. It is involved in the negative regulation of complement activation. B5 binds to complement components C3 and C1q, blocking complement activation at multiple sites and downregulating pro-inflammatory chemotactic factors (C3a, C4a, and C5a), thereby reducing cellular influx and inflammation. B5 is conserved in various Orthopoxviruses and B5 antibodies and can protect the host from vaccinia virus attack. B5 antibodies can neutralize vaccinia EV, although the mechanism is unclear. Studies have shown that monoclonal human anti-B5 IgG is heavily dependent on IgG binding to complement C3 and C1q. Similarly, complement-binding IgG controls the complement-dependent cytotoxicity of infected cells. Human polyclonal antibodies induced by smallpox vaccines also rely on complement to neutralize EV and depend on complement to destroy infected cells.
References
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3.Ward BM, Weisberg AS, Moss B. J. Mapping and functional analysis of interaction sites within the cytoplasmic domains of the vaccinia virus A33R and A36R envelope proteins[J]. Virol., 2003, 77: 4113-26.
4.Law M, Hollinshead R, Smith GL. J. Gen. Antibody-sensitive and antibody-resistant cell-to-cell spread by vaccinia virus: role of the A33R protein in antibody-resistant spread[J]. Virol., 2002, 83: 209-222.
5.Smith SA, Sreenivasan R, Krishnasamy G, et al. Mapping of regions within the vaccinia virus complement control protein involved in dose-dependent binding to key complement components and heparin using surface plasmon resonance[J]. Biochim. Biophys. Acta, 2003, 1650: 30-39.
6.Paran N, Lustig S. Complement-bound human antibodies to vaccinia virus B5 antigen protect mice from virus challenge[J]. Expert Rev Vaccines, 2010, 9: 255-259.
7.Iyer LM, Aravind L, Koonin EV. J. Common origin of four diverse families of large eukaryotic DNA viruses[J]. Virol., 2001, 75: 11720-34.
8.Bisht H, Weisberg AS, Moss B. Vaccinia virus l1 protein is required for cell entry and membrane fusion[J]. J Virol., 2008, 82(17): 8687-94.
