Most of the information on orthopoxviruses innate immune evasion comes from research on VACV and the suppression of the host antiviral immune response. The antiviral immune response, mediated by cellular IFN, is strongly inhibited by the E3L gene of VACV (Weaver and Isaacs, 2008). To prevent activation of known pattern recognition receptors such as protein kinase R, MDA-5, RIG-I, and OAS, the E3 protein can bind double-stranded RNA and secrete it from them. An N-terminal Z-nucleic acid binding domain and a C-terminal dsRNA-binding domain form the two conserved domains of the VACV-E3 protein (Xu et al., 2008). In a mouse model and in vitro, wild-type virus pathogenesis depends on these two domains. The PKR pathway can be completely inhibited only when the N-and C-terminal domains of the VACV-E3 protein are present (Arndt et al., 2015; Shafaati and Zandi, 2022a).

Two VACV recombinants, VACV-E3L83N (which has the first 83 amino acids of the N terminus of E3L removed) and VACV-E3L37N (which encodes only the smaller of the two proteins [p20] translated from E3L mRNA), have been shown in in vitro studies to have similar host range and IFNr phenotype to wild-type VACV in most cells in culture (Edghill-Smith et al., 2005). However, VACV-E3L83N and VACV-E3L37N were 100–1,000 times less pathogenic than wild-type VACV in an animal model. Phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2) was observed in cell lines infected with either virus at a late times point (9 h postinfection), but not in wild-type VACV-infected HeLa cells (Shafaati and Zandi, 2022c).

Genomic studies revealed sequence similarities between MPXV and VACV. With 92% nucleotide and 88% protein sequence similarity, the F3 protein of MPXV and E3 protein of VACV are homologous to each other (Arndt et al., 2015). According to the MPXV genome sequence, the C-terminal dsRNA-binding domain of the F3 protein is intact and functional, but the first 37 amino acids of the Z-NA binding domain are missing (Yuwen et al., 1993; Langland and Jacobs, 2004). According to Arndt et al., the MXPV genome encodes a modified E3 homolog. MPXV is identical to wild-type VACV in terms of IFNr and host range and can suppress the cellular antiviral immune response more effectively than a VACV mutant with an identical N-terminal deletion in E3. These results suggest that MPXV can prevent symptoms caused by the absence of an N-terminal region in its E3 homolog (Resch et al., 2007). The failure of VACV to completely inhibit PKR or restore replication in cells in culture when F3l is replaced by E3L indicates that inhibition of the absence of an N-terminal domain of F3 is extragenic (Arndt et al., 2015; Lum et al., 2022; Figure 1).

In addition, cowpox virus (CPV), another orthopoxvirus, has been shown to inhibit intracellular transport of MHC class I, a process associated with CPV evasion of the CD8+ T-cell antiviral responses (Komiyama et al., 1994). CPV ORF203 has been shown to maintain MHC class I at ER. However, MPXV encoding a near-homologous CPV ORF203 cannot downregulate MHC Class I. Instead, it can employ an evasion strategy to block activation of CD4+ and CD8+ T-cells after cognate contacts with MPXV-infected cells (Shchelkunov, 2012). This strategy of suppressing local T-cell responses could avoid systemic immunosuppression while hiding the viral reservoir from immunological surveillance. By using a specific mechanism to bypass the immune system, MPXV can avoid both CD4+ and CD8 + T-cell responses, which are antiviral (Song et al., 2013). The inability of T-cells to respond is an MPXV-infected cell-dependent and MHC-independent phenomenon. This implies that MPXV encodes an immunomodulator that blocks antiviral T-cell responses that are activated either directly or indirectly by the host. This inhibition is likely critical for viral pathogenicity as well as for systemic transmission of cell-associated viruses (Lum et al., 2022). It may be possible to understand why mpox can spread rapidly as a type of cell-associated viremia by studying the mechanism by which virus-specific T-cells bypass immune surveillance. Neutralizing antibodies to orthopoxviruses are critical for protection against severe infections, and systemic proliferation in circulating monocytes may also protect the virus from humoral immune responses, explaining why vaccinated monkeys are protected. Memory T-cells specific for orthopoxviruses do not provide protection against lethal mpox in the absence of neutralizing antibodies (Shafaati and Zandi, 2022c). After recovery from mpox, individuals may activate antiviral T-cell responses. Although there is an immune evasion mechanism that strongly inhibits T-cells from recognizing monkeypox virus. The endogenous T-cell response is triggered indirectly by infected monocytes through the presentation of an alternative antigen and/or cross priming (Cho and Wenner, 1973; Slifka, 2004; Edghill-Smith et al., 2005). Neutralizing antibodies must also be present to prevent virulent orthopoxvirus infections. Circulating monocytes, through which virus spreads throughout the body, may protect it from the effects of virus-specific humoral immunity (Hammarlund et al., 2008).

Immunity to mpox is typically determined by studying interactions between various orthopoxviruses like the vaccinia virus (VACV). It has been proposed that the poxvirus antigen on neutrophils and monocytes significantly determines mpox mortality. It was also found that primary human M2-like macrophages support VACV replication and transmission. After becoming infected, these primary macrophages produced actin tails, cell junctions, lamellipodia, and branching structures related to VACV virions, indicating that these cells may aid in the spread of the MPXV (Hammarlund et al., 2008; Rubins et al., 2011). A similar strategy could be used by a monkeypox virus to evade the host’s immunity. Because several innate immune cells, including monocytes or macrophages, neutrophils, natural killer cells, dendritic cells, and innate lymphoid cells, have not yet been identified. A smallpox vaccination also provides cross-protection against mpox (Zandi et al., 2022). There is a significant degree of sequence similarity among orthopoxviruses, especially in immunologically significant proteins, leading to numerous shared immune epitopes. T cell responses (CD4+ and CD8+ T cells) can identify epitopes on a wide range of viral proteins. People with mpox may get post-exposure prophylaxis, such as vaccination, immune globulin, or antiviral therapies. Jynneos and IMVANEX vaccines are used to provide protective immunity against mpox (Shafaati and Zandi, 2022c).