Neoplasia: could iciHHV-6A cause a benign HPV strain to turn deadly?

In All, Cancer, ciHHV-6 by Kristin Loomis

Human Papillomavirus (HPV) 4 typically does not cause severe neoplasia in the genital tract. In this case, a high grade vaginal squamous lesion developed rapidly in a woman with inherited chromosomally integrated HHV-6A. The authors warn that the two viruses may have a synergistic effect and that individuals with inherited HHV-6A should be followed closely.

HPV4 is not considered to be one of the carcinogenic strains of the virus, and has only been associated with plantar warts. Two of the high-risk HPV types, 16 and 18, account for between 70 and 95% of cervical, anal, and oropharyngeal cancers. HPV strains were found in 96% of vaginal intraepithelial neoplasia in a study of 189 cases, but none of them were found to be HPV4 (Alemany 2014).

IciHHV-6A can reactivate and produce infectious virus, as has been described in the case of an infant with an activated inherited strain and severe combined immune deficiency (Endo 2014). Pregnant women with iciHHV-6 can also pass infectious virus to their fetuses transplacentally (Gravel 2013).

Potential triggers for iciHHV-6A reactivation include HDAC inhibitors and high dose steroids. A recent case report described possible activation of iciHHV-6B in response to high dose progesterone (Das 2016).

Herpesviruses including HHV-6 have been suggested as possible cofactors in HPV related oncogenesis (Szostek 2009), and HHV-6 was previously found to be associated with high-grade squamous intraepithelial lesions of the cervix with an odds ratio of 10.9 (95% confidence level), but not after controlling for HPV (Tran-Thanh 2002). In another study, the presence of HHV-6 in HPV-infected women correlated with a higher grade of squamous intraepithelial lesions, and while none of the normal HPV+ cervixes were infected with HHV-6, 41% of high-grade lesions were infected with HHV-6 (Broccolo 2008). HHV-6 has been shown to productively infect HPV-immortalized cells, transactivate HPV gene expression of oncoproteins, and enhance the expression of HPV RNAs (Chen 1994, Romano 1996, Wang 1994).

Read the full paper: Pichon 2017.