The role of herpesviruses in development of diseases of the urogenital tract and infertility in women

Abstract

This review presents the data on the spreading of all known human herpesviruses (НHVs) in female urogenital tract. According to the WHO almost 500 million people worldwide suffer from genital infection caused by НHVs. НHVs were detected in various inflammatory diseases of female upper and lower genital tract (vaginitis and cervicitis), in extrauterine pregnancy (in fallopian tubes), in infertility (cervical channel, endometrium and ovaries). Herpes simplex virus 1 (HSV‑1) was identified for the first time in oocytes after failed in vitro fertilization (IVF). НHVs produce negative effect on the entire reproductive process from conception to childbirth. It was established that HSV, cytomegalovirus (CMV) and human herpesvirus 6 (HHV-6) markedly increase the risk of spontaneous abortion, preterm birth and stillbirth. Intrauterine НHV infection is a major cause of congenital malformations. Data on humoral and cell immunity in genital herpesvirus infections (НHVI) are also reviewed. Intravaginal HSV‑2 infection changes cell composition of vaginal mucosa, i.e., together with cells mobilized from the blood, protective role is performed by resident memory T‑cells (TRM), natural killer cells (NK‑cells) and regulatory T‑cells (Treg) whose function consists in maintaining the balance of the activities of lymphocytes. Constant НHVI spreading is largely explained by transition of primary infection to potentially reactivating latent form, since latent virus is unavailable to immune recognition and medicines. The genome editing system CRISPR/Cas9 can recognize and modify not only active but also latent viruses. The promising pilot results with the use of this system offer the possibility of developing innovative technologies for НHV elimination and НHVI eradication.

Intravaginal delivery for CRISPR–Cas9 technology: For example, the treatment of HPV infection

“…Therefore, preventive HSV treatment is urgently needed. Palliser et al 20 suggested that CRISPR/Cas9 combined with vaginal administration against HSV virus envelope glycoprotein B and virus DNA binding protein could protect mice from HSV infection. Mice treated with CRISPR/Cas9 successfully silenced gene expression for 9 days and 2 h before and 4 h after HSV‐2 vaginal challenge.…”

“…[12][13][14][15][16][17] Delivery of siRNA targeting UL 39 and DNA polymerase genes in HSV-1 has been proved to effectively and specifically knockdown the corresponding gene expression and inhibit HSV-1 replication in vitro. 18,19 In addition, CRISPR/Cas9based microbicides effectively protect mice from HSV-1 infection when administered intravenously 20 ; this finding will be discussed in detail later in this review. With respect to HPV, over 90% of human cervical cancers are a result of abnormal cell proliferation driven by HPV oncoproteins.…”

Complete and Prolonged Inhibition of Herpes Simplex Virus Type 1 Infection In Vitro by CRISPR/Cas9 and CRISPR/CasX Systems

“…There is evidence that HSV-1 may be involved in the development of such neuropathologies as Alzheimer’s disease [ 4 ], multiple sclerosis [ 5 ], meningitis and encephalitis [ 6 ]. As other sexually transmitted infections, HSV-1 genital herpes may contribute to the development of infertility, negatively affect pregnancy, up to fetal death, cause congenital and neonatal infections [ 7 , 8 ]. Reactivation of herpesviruses has also been observed in patients infected with SARS-CoV-2 [ 9 , 10 ], the causative agent of the ongoing COVID19 pandemic [ 11 ].…”

Medicinal plants and natural compounds against acyclovir-resistant HSV infections

“…HSV infections have become a major public health concern. According to a WHO investigation, more than one billion people worldwide are infected with HSV-1-caused oral herpes, and an estimated 500 million are infected with HSV-2caused genital herpes (Kushch et al, 2021). Acyclovir (ACV) is widely used to treat HSV infections and inhibits HSV-specific DNA polymerase and impedes HSV replication and further infection (Brigden and Whiteman, 1983).…”

“…HSV infections have become a major public health concern. According to a WHO investigation, more than one billion people worldwide are infected with HSV-1-caused oral herpes, and an estimated 500 million are infected with HSV-2-caused genital herpes ( Kushch et al, 2021 ).…”