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Microbes & Immunity Correlation between VZV and cancer

BH3 interacting domain death agonist, cytochrome C, VZV, causing downregulation of the expression of the
and apoptotic protease activating factor-1; and ligands antigen presentation molecule, disrupting the cytokine
and receptors associated with apoptosis, such as tumor response responsible for the connection between the
necrosis factor-alpha (TNF-α), TNFR1, TRAIL-R, and innate and adaptive immune responses. Reports have
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interleukin-1 (IL-1). The authors conclude that neurons shown that CD1d downregulation and disappearance are
infected with VZV do not undergo apoptosis, whereas seen in late-stage cancer progression. An increase in
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other cells do. 47 these key cell cycle regulators has been detected in many
types of cancers, including many cancers discussed in
3.1. Survivin’s effect on the immune system this discussion. Reports of epidermal hyperplasia found
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Inhibition of apoptosis is one of the many biological on skin biopsies support the possibility of increased cell
mechanisms in cancer manifestation and has been linked proliferation caused by the cell cycle dysregulation caused
to multiple cancers. Survivin, one of the genes associated by VZV. 60
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with the inhibition of apoptosis, plays a key role in the
intrinsic pathway of apoptosis, serving as an inhibitor of 3.2. ORF’s effects on the immune system
caspase-9, effector caspase-3, and effector caspase-7. The 3.2.1. Downregulation of IFN-β
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interaction interrupts the caspase cascade and cleavage VZV’s genome contains over 70 distinct open reading
process, leading to reduced apoptosis. Another mediator frames (ORFs), each of which encodes proteins that
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affected by survivin and that plays a role in apoptosis is contribute to various aspects of viral pathogenesis.
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the mitochondrial protein apoptosis-inducing factor These include structural proteins that form the viral
(AIF). Survivin prevents the release of AIF from the particle, enzymes that aid in viral DNA replication, and
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mitochondrial intermembrane space and its movement regulatory proteins that help the virus evade the host
to the nucleus, thereby blocking caspase-independent immune system or facilitate the transition to latency.
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apoptosis. Furthermore, survivin overexpression in ORF66 phosphorylates the IE62 protein, the gene product
human lung cancer cells inhibits p53-dependent apoptosis, of ORF12, preventing the nuclear import of IE62, causing
suggesting it regulates the p53-dependent apoptotic it to accumulate in the cytoplasm. The cytoplasmic
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pathway. Similar findings between altered expression of accumulation of IE62 has significant implications by
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p53 and survivin in oral squamous cell carcinoma were causing the inhibition of IFN regulatory factor 3 (IRF3)
noted by Aggarwal et al. where there was a significantly phosphorylation by TANK-binding kinase 1 (TBK1),
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higher level of both p53 and survivin in the experimental which is crucial for IRF3 activation. This inhibition prevents
group versus the control group. Altering survivin’s function IRF3 from undergoing the necessary conformational
has provided strong evidence of its role in apoptosis, changes required for its dimerization and nuclear
as a mutation in survivin (T34A) triggers the release of translocation. Without phosphorylation, IRF3 cannot
cytochrome c from the mitochondria, thereby promoting bind to the IFN-β promoter or activate the transcription
apoptosis. It is through these mechanisms that survivin of IFN-β (Figure 1). IFN-β plays a crucial role in the
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plays a critical role in inhibiting apoptosis by blocking key host’s immune response, serving as a key mediator in
pro-apoptotic events and promoting cell survival under the defense against viral infections and malignant cells;
stressful conditions, contributing to its involvement in therefore, inhibition of IFN-β production through TBK1-
oncogenesis. Further investigations into the mechanism mediated processes leaves the host susceptible to cancer
of VZV’s ability to induce oncogenesis in non-neuronal manifestation. 67
cells through survivin-manipulating pathways need to be
conducted, especially considering that it is only neuronal 3.2.2. ORF66’s role in preventing apoptosis
cells that experience anti-apoptotic effects, but these cells VZV gene products, including ORF66, are involved in
have not been reported to show a significant increase in inhibiting apoptosis. Specifically, ORF66 prevents apoptosis
cancer development compared to non-neuronal cells. in T cells, as T cells infected with a virus lacking functional
Investigations into the effects VZV has on the cell ORF66 protein are more prone to undergoing apoptosis
cycle of human foreskin fibroblasts determined the through unspecified mechanisms. In addition, ORF66 also
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2
dysregulation of multiple key regulatory proteins. modulates caspase 8 and IFN-γ antiviral effects. Finally,
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In VZV-infected confluent fibroblasts, there was an previous studies have shown that ORF66 sequesters major
unusual increase in the levels of CDK1, CDK2, cyclin B1, histocompatibility complex (MHC) class I molecules in the
cyclin D3, and cyclin A proteins, along with significant Golgi of infected MeWo cells and fibroblasts; however, the
activation of CDK2, CDK4, and cyclin B1 kinase viral gene product(s) and molecular mechanisms involved
activities. Further, CD1d transcription is targeted by in modulation of cell-surface immune molecule expression
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Volume 2 Issue 3 (2025) 18 doi: 10.36922/mi.8320