From infection to infertility: a review of the role of human papillomavirus-induced oxidative stress on reproductive health and infertility

Abstract

Infertility has emerged as a significant global health concern, affecting nearby 8-12% of couples in reproductive age worldwide. Increasing evidence suggests a potential link between human papillomavirus (HPV) and infertility in both men and women. Some research indicate that HPV can infect various components of semen, potentially affecting sperm quality by decreasing motility, viability, and increasing DNA fragmentation, all of which may contribute to male infertility. The virus can attach to the equatorial region of the sperm head, enabling infected sperm to transmit the virus to the oocyte or placenta. Consequently, HPV potentially induces apoptosis in trophoblastic cells and disrupts their adhesion to endometrial cells, which raises the risk of miscarriage. HPV may also affect ovarian reserve by causing chronic inflammation, which can impair granulosa cell function and lower serum anti-Müllerian hormone (AMH) levels. Besides, HPV-related immune responses also contribute to infertility by producing anti-sperm antibodies (ASAs), which cause sperm clumping, reduce motility through cervical mucus, activate the complement system that damages sperm in the female reproductive tract and interfere with sperm-egg interactions. Moreover, HPV infection has been linked to reduced success rates in assisted reproductive technologies (ART), potentially disrupting critical processes such as the acrosome reaction, sperm-oocyte interaction, and fusion. One potential mechanism through which HPV contributes to infertility is oxidative stress (OS). Triggered OS can negatively impact sperm quality and cause damage to the female reproductive system, ultimately contributing to infertility. Despite these associations, the precise mechanisms and the strength of the relationship remain uncertain. Thus, this review seeks to investigate the potential impact of HPV on infertility, particularly its effects on the reproductive system through OS. A clearer understanding of these processes could inform future health strategies for addressing HPV-related infertility.

Keywords: Human papillomavirus; Infertility; Inflammation; Oxidative stress; Reproductive health; Reproductive tract infections.

Fig. 1

The pathways associated with oxidative stress (OS) and cellular damage induced by human papillomavirus (HPV) proteins. The E2 protein interacts with mitochondrial membrane proteins (e.g., complex III), leading to the release of reactive oxygen species (ROS) from mitochondria. Co-expression of E1 and E2 proteins further elevates ROS production while reducing levels of antioxidants such as glutathione (GSH) and superoxide dismutase 2 (SOD2), resulting in increased DNA damage markers like phospho-histone 2 AX (γH2 AX). The E6 oncoprotein decreases antioxidant levels, including GSH and catalase, and a spliced variant of E6 inhibits antioxidant enzymes such as SOD2 and Gpx1/2. The E6/E7 oncoproteins activate nicotinamide adenine dinucleotide phosphate oxidases (NOXs), particularly NOX2, enhancing ROS production, which contributes to DNA damage and chromosomal instability. Additionally, E6/E7 inhibit the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, reducing the activity of cytoprotective enzymes and exacerbating OS. These pathways collectively lead to apoptosis, autophagy, lipid peroxidation, DNA damage, protein damage, and inflammation, which are critical for the development and progression of HPV-associated cancers

Fig. 2

The impact of human papillomavirus (HPV) infection on the male reproductive system and sperm quality. HPV infection in the male genital tract (MGT) is associated with increased viral load in the testis and epididymis, leading to an elevated risk of penile and testicular cancer, and reduced fertility. It also suggests potential co-infections with pathogens such as Ureaplasma, Urealyticum, Nontuberculous epididymitis, and HIV, which may exacerbate inflammation and oxidative stress (OS) in the reproductive tract and elevated risks of infertility. HPV DNA is detectable in all components of semen, including sperm cells, somatic cells, and seminal plasma. The infection in semen induces inflammation, recruiting immune cells and triggering the production of pro-inflammatory cytokines such as IL-1, IL-6, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ), which collectively contribute to reactive oxygen species (ROS) generation and OS. The resulting OS leads to increased DNA fragmentation, elevated pH levels, and abnormal sperm morphology. Furthermore, it negatively impacts hormonal and seminal parameters, including reduced testosterone levels, decreased semen volume, impaired sperm motility and viability, and lower total sperm count and concentration. In sperm cells, the interaction of HPV proteins, such as HPV-E2, with mitochondrial membrane proteins, leading to mitochondrial ROS release and OS. Co-expression of E1 and E2 proteins further exacerbates ROS production, increases DNA damage markers like γH2 AX, while decreasing glutathione (GSH) levels and superoxide dismutase 2 (SOD2) activity. Additionally, the disruption of AQP8 by the viral L1 protein impairs water and hydrogen peroxide (H₂O₂) transport and detoxification processes, contributing to sperm stress and functional impairment. HPV infection also leads to the production of ASA. HPV-infected sperm cells act as carriers for HPV antigens, initiating or boosting a humoral immune response in HPV-naïve or HPV-experienced women, respectively. This immune response can result in the antibody-mediated elimination of both HPV-infected and uninfected sperm cells, further compromising fertility. The interplay between ASA and anti-HPV antibodies, and their contribution to infertility, remains an area for further investigation

Fig. 3

The effects of HPV infection on female reproductive health. HPV infection disrupts the vaginal microbiome, leading to microbial dysbiosis and an imbalance in vaginal flora. It also negatively impacts ovarian reserve by impairing granulosa cell function, resulting in decreased serum anti-Müllerian hormone (AMH) levels, particularly in HPV-positive patients, with more pronounced effects in advanced cervical intraepithelial neoplasia (CIN III) cases. Additionally, HPV promotes apoptosis in trophoblastic cells and hinders their adhesion to endometrial cells, increasing the risk of miscarriage. Furthermore, HPV infection is associated with reduced success rates in assisted reproductive technology (ART) and a higher likelihood of adverse pregnancy outcomes. Finally, there is the potential role of OS pathways induced by HPV, which may contribute to the observed effects on fertility, including impaired oocyte quality, blastocyst development, and endometrial receptivity. However, the exact mechanisms linking OS to infertility remain unclear and require further research