Genetic instability and anti-HPV immune response as drivers of infertility associated with HPV infection

Abstract

Human papillomavirus (HPV) is a sexually transmitted infection common among men and women of reproductive age worldwide. HPV viruses are associated with epithelial lesions and cancers. HPV infections have been shown to be significantly associated with many adverse effects in reproductive function. Infection with HPVs, specifically of high-oncogenic risk types (HR HPVs), affects different stages of human reproduction, resulting in a series of adverse outcomes: 1) reduction of male fertility (male infertility), characterized by qualitative and quantitative semen alterations; 2) impairment of couple fertility with increase of blastocyst apoptosis and reduction of endometrial implantation of trophoblastic cells; 3) defects of embryos and fetal development, with increase of spontaneous abortion and spontaneous preterm birth. The actual molecular mechanism(s) by which HPV infection is involved remain unclear. HPV-associated infertility as Janus, has two faces: one reflecting anti-HPV immunity, and the other, direct pathogenic effects of HPVs, specifically, of HR HPVs on the infected/HPV-replicating cells. Adverse effects observed for HR HPVs differ depending on the genotype of infecting virus, reflecting differential response of the host immune system as well as functional differences between HPVs and their individual proteins/antigens, including their ability to induce genetic instability/DNA damage. Review summarizes HPV involvement in all reproductive stages, evaluate the adverse role(s) played by HPVs, and identifies mechanisms of viral pathogenicity, common as well as specific for each stage of the reproduction process.

Keywords: DNA damage; Gastrulation; Genomic instability; Human papilloma viruses of high oncogenic risk type; Infertility; Oocyte; Reproductive health; Sperm cells; Spontaneous abortion; Viral integration.

Fig. 1

Schematic representation of the stages of fertilization and embryonal development. Infertility may originate from defects in production and/or functionality of gametes, fertilization, early development of the embryo, its placentation, as well as the late stages of embryonal development. Figure elements are adapted from [1, 2] and Human placental project at https://www.nichd.nih.gov/research/supported/HPP/form

Fig. 2

Stages of the fertilization and embryonal development compromised by HPV infection. Cells, tissues and embryo infected with HPVs at different stages of development are colored in grey tones. Black cross designates preterm termination of the embryonal development. Spontaneous clearance of HPVs from the epithelial tissues is well documented; no data exists on possibility of HPV clearance from the infected embryonal cells and/or fetus, this possibility is not excluded and is designated on the scheme with a question mark. Elements of the figure are adapted from [1, 2], Human placental project at https://www.nichd.nih.gov/research/supported/HPP/form and image of five month human fetus corresponding to the successful passage of 20 weeks of pregnancy (no spontaneous/preterm abortion), from https://www.pinterest.com/pin/441352832202220770/