Role of Epstein-Barr Virus and Human Papillomavirus Coinfection in Cervical Intraepithelial Neoplasia in Chinese Women Living With HIV

Abstract

Given that only a small percentage of human papillomavirus (HPV)-positive women develop cancer, HPV is necessary but insufficient for carcinogenesis. Mucosally transmitted viral cofactors appear to contribute to HPV-related cervical cancer, such as Epstein-Barr virus (EBV), but previous studies have shown inconsistent outcomes. The exact role of EBV in cervical cancer remains unclear, and more studies are needed to determine its involvement. In this study, we describe the prevalence of EBV and HPV coinfection in HIV-positive women and explore how abnormal host immune status induced by viral coinfections modulates epithelial gene expression. We found a significant correlation between EBV-HPV coinfection and the incidence of high-grade cervical intraepithelial neoplasia (CIN2+). RNA sequencing indicated that CIN tissues coinfected with EBV and HPV led to significant changes in the gene expression of epithelial differentiation and development compared to normal tissues with HPV infection alone. In particular, several differentially expressed genes (DEGs) are closely associated with cancer, such as CACNG4, which was confirmed to be upregulated at both the mRNA and protein levels. Therefore, these findings provide some evidence that EBV may act as a cofactor or mediator in HPV-related cervical cancer. Specific genes or proteins, such as CACNG4, may serve as biomarkers that can risk stratify patients based on pathological changes in the cervix.

Coinfections with additional oncoviruses in HPV+ individuals: Status, function and potential clinical implications

“…Feng et al studied HIV+ Chinese women and found that women who were HPV/EBV positive had a higher incidence of high-grade cervical intraepithelial neoplasia. 23 It should be noted that HIV infection may increase the incidence of HPV/EBV coinfection and HPV-related malignancies due to compromised cellular immunity. In a study of Iranian women, Joharinia et al reported similar trends.…”

“…This group then looked at a new cohort of 295 HIV+ women, and they found that hrHPV infection alone did not significantly correspond to SIL incidence, but dual hrHPV/EBV positivity once again showed high association with SIL (~fourfolds increase from hrHPV+ alone). Feng et al studied HIV+ Chinese women and found that women who were HPV/EBV positive had a higher incidence of high‐grade cervical intraepithelial neoplasia 23 . It should be noted that HIV infection may increase the incidence of HPV/EBV coinfection and HPV‐related malignancies due to compromised cellular immunity.…”

HPV co‐infections with other pathogens in cancer development: A comprehensive review

“…The vIL‐10 inhibits IFN‐γ, IL‐2, IL‐6, TNF‐α, and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) production by CD4 + T lymphocytes and monocytes resulting in immune evasion of infected epithelial cells 104 . vIL‐10 impairs monocyte maturation and host natural defense system against viral infections 113 . IL‐10 induced by HPV E2, E6, and E7 proteins and vIL‐10 activate Janus kinase/STAT3 cascade that leads to reduction of TNF‐α, IL‐6, and IL‐1β expression interfering with the NF‐κB signaling pathway with increased tumorigenic and metastatic ability and epithelial‐mesenchymal transition (EMT) 111,114 .…”

How Does Epstein–Barr Virus Interact With Other Microbiomes in EBV-Driven Cancers?

“…It still remains to be explored whether the coinfection is the etiology or just a phenomenon which is not causality. HPV/EBV coinfection was reported to present in some of prostate cancer (PCa) cases ( Nahand et al., 2021 ), oral carcinogenesis ( Blanco et al., 2021 ), cervical cancer ( Feng et al., 2021 ), breast cancer ( Nagi et al., 2021 ), and nasopharyngeal carcinoma (NPC) ( Blanco et al., 2021 ) (shown in Table 1 ). The cytokine expression profile of PCa cases with HPV and EBV coinfection was quite different from that only infected with HPV or EBV.…”