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Microbes & Immunity Correlation between VZV and cancer

various genes involved in these cellular processes. In immune suppression, such as through the upregulation
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the context of VZV latency and reactivation, studies have of immune checkpoint receptors and ligands such as
shown that VZV infection activates the JNK pathway, programmed cell death protein 1 (PD-1) and programmed
which is essential for efficient viral protein expression and death-ligand 1 (PD-L1), and subsequent VZV reactivation,
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replication. Specifically, the activation of JNK following which could facilitate tumor development. In addition,
VZV infection leads to the phosphorylation of c-Jun, the inflammatory response triggered by HZ infection
which is crucial for the transactivation of viral genes through the release of pro-inflammatory cytokines, along
necessary for lytic infection and reactivation. Interestingly, with the virus’s effects on cellular pathways associated
inhibition of the JNK pathway in melanoma cells led to an with cancer, such as JAK-STAT, NFκB, and TNF-α, likely
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increase in VZV replication but resulted in a decrease plays a role in this increased risk. Research has shown
in replication in fibroblasts, suggesting that the role of that the 1 year following HZ infection is a crucial period
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JNK in VZV pathogenesis depends upon the type of cell for cancer risk. For example, a population-based study
infected. Furthermore, inhibition of the JNK pathway conducted by Sorensen et al. reported an RR of 4.0 in
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has been shown to block viral replication and significantly the first 3 months of hospitalization due to HZ, which
reduce reactivation in human neuronal models. Zapata decreased over time but remained elevated at 2.1 between
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et al. found that the competitive inhibitor SP600125 9 and 12 months. The RR further declined to 1.9 between
effectively reduced VZV yield in human fibroblast cells 1 and 5 years, and 1.3 between 5 and 10 years with a
by eliminating phosphorylated c-Jun, thereby confirming higher prevalence of distant metastases within 1 year of
the specificity and efficacy of the inhibitor. Further studies follow-up compared to control groups when considering
with SP600125 resulted in a marked reduction in VZV multiple cancer types. Of note, because the population
reactivation, indicating that the JNK pathway is critical used in this study is hospitalized individuals, the results
for the reactivation process. These findings underscore in this report may be subject to selection bias, reverse
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the critical role of the JNK pathway in VZV replication causality, or confounding by comorbidity. Cotton et al.
and reactivation, highlighting SP600125 as a potential accounted for this in their retrospective cohort study
therapeutic agent for controlling VZV reactivation and of a primary care population, where they also found an
related diseases. increased risk of cancer diagnosis within the first 90 days
when controlling for patients using immunosuppressive
5. VZV in cancer agents. Mahale et al. state similar findings reporting
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5.1. VZV in cancer overview that HZ was significantly associated with several cancers
when diagnosed 13 – 35 months before cancer diagnosis
VZV’s ability to manipulate host cell functions, evade or control selection. A meta-analysis published by Schmidt
immune surveillance, and remain dormant in a latent et al. reviewed 46 studies investigating an association
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state raises questions about its potential role in the onset between HZ and cancer, reporting an overall RR of 1.42 for
and progression of certain cancers. While VZV is not any type of cancer and 1.83 for the risk of cancer following
traditionally classified as an oncogenic virus such as 1 year after an HZ diagnosis. These findings highlight the
human papillomavirus or Epstein-Barr virus (EBV), importance of the 1 year after HZ infection as a critical
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emerging research has suggested its involvement in tumor window for cancer risk, though further studies are needed
development. Specifically, VZV’s ability to trigger chronic to better understand the underlying mechanisms that
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inflammation and interact with cancer-associated contribute to this elevated risk. 105
pathways may contribute to the formation of malignant A case–control study done on the U.S. elderly population
lesions. Cotton et al. outline some of the earliest ages ≥65 reported similar results of an increased cancer
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publications linking VZV infection to cancer diagnosis, diagnosis with HZ infection in 2016 when investigating
noting that while early studies failed to establish a clear the link of VZV infection to 48 different cancer types.
association, recent evidence indicates otherwise, but due Hematologic malignancies had a higher association with
to differences in methods, demographics, and cancer types cancer diagnosis versus solid tumor malignancy in HZ
reported by various articles on this topic, it is still difficult patients. Stages of solid tumors of the cancers diagnosed
to determine if there is a clear association between VZV in this study were also reported which most papers on
infection and cancer diagnosis.
this topic fail to report. HZ was most strongly associated
One critical observation is the increased relative risk (RR) with solid cancers diagnosed at regional or distant stages.
of certain cancers, particularly hematologic malignancies Significant associations were found for regional stage
such as lymphoma and leukemia, in the 1 year following colon cancer (OR: 1.13), non-melanoma skin cancer
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HZ infection. This heightened risk may be linked to (OR: 1.97), and distant stage oral cavity/pharyngeal cancer
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Volume 2 Issue 3 (2025) 22 doi: 10.36922/mi.8320