Herpes Simplex Virus, Human Papillomavirus, and Cervical Cancer: Overview, Relationship, and Treatment Implications.

There is a significant body of research examining the role of human papillomavirus (HPV) in the pathogenesis of cervical cancer, with a particular emphasis on the oncogenic proteins E5, E6, and E7. What is less well explored, however, is the relationship between cervical cancer and herpes simplex virus (HSV). To date, studies examining the role of HSV in cervical cancer pathogenesis have yielded mixed results. While several experiments have determined that HPV/HSV-2 coinfection results in a higher risk of developing cervical cancer, others have questioned the validity of this association. However, clarifying the potential role of HSV in the pathogenesis of cervical cancer may have significant implications for both the prevention and treatment of this disease. Should this relationship be clarified, treating and preventing HSV could open another avenue with which to prevent cervical cancer. The importance of this is highlighted by the fact that, despite the creation of an effective vaccine against HPV, cervical cancer still impacts 604,000 women and is responsible for 342,000 deaths annually. This review provides an overview of HSV and HPV infections and then delves into the possible links between HPV, HSV, and cervical cancer. It concludes with a summary of preventive measures against and recent treatment advances in cervical cancer.

Anemia prevalence time trends and disparities in the US population: examination of NHANES 1999-2020.

While a rising prevalence of anemia in the United States was reported in older studies, recent data are lacking. To estimate the prevalence and time trends of anemia in the United States and to examine how these estimates differ by gender, age, race, and household income to poverty threshold ratio (HIPR), we used the National Health and Nutrition Examination Surveys from 1999 to 2020. The presence of anemia was determined using the World Health Organization criteria. Survey-weighted raw and adjusted prevalence ratios (PRs) were determined using generalized linear models for the overall population and by gender, age, race, and HIPR. In addition, an interaction between gender and race was explored. Complete data on anemia, age, gender, and race were available on 87,554 participants (mean age = 34.6 years, women = 49.8%, Whites = 37.3%). Anemia prevalence increased from 4.03% during the 1999-2000 survey cycle to 6.49% during 2017-2020. In adjusted analyses, anemia prevalence was higher in >65 than in 26-45 years old (PR = 2.14, 95% confidence interval (CI) = 1.95, 2.35), in Blacks than Whites (PR = 3.97, 95% CI = 3.63, 4.35), in women than men (PR = 1.98, 95% CI = 1.83, 2.13), and in those with HIPR ≤ 1 than >4 (PR = 0.68, 95% CI = 0.61, 0.75). Gender modified the relationship between anemia and race; when compared to their male counterparts, Black, Hispanic, and other women had higher anemia prevalence than White women (all interaction p values <0.05). The anemia prevalence in the United States has risen from 1999 to 2020 and remains high among the elderly, minorities, and women. The difference in anemia prevalence between men and women is larger in non-Whites.

MDA5-dependent responses contribute to autoimmune diabetes progression and hindrance.

Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic ß cell destruction. Coxsackievirus B3 (CVB3) infection and melanoma differentiation-associated protein 5-dependent (MDA5-dependent) antiviral responses are linked with T1D development. Mutations within IFIH1, coding for MDA5, are correlated with T1D susceptibility, but how these mutations contribute to T1D remains unclear. Utilizing nonobese diabetic (NOD) mice lacking Ifih1 expression (KO) or containing an in-frame deletion within the ATPase site of the helicase 1 domain of MDA5 (ΔHel1), we tested the hypothesis that partial or complete loss-of-function mutations in MDA5 would delay T1D by impairing proinflammatory pancreatic macrophage and T cell responses. Spontaneous T1D developed in female NOD and KO mice similarly, but was significantly delayed in ΔHel1 mice, which may be partly due to a concomitant increase in myeloid-derived suppressor cells. Interestingly, KO male mice had increased spontaneous T1D compared with NOD mice. Whereas NOD and KO mice developed CVB3-accelerated T1D, ΔHel1 mice were protected partly due to decreased type I IFNs, pancreatic infiltrating TNF+ macrophages, IFN-γ+CD4+ T cells, and perforin+CD8+ T cells. Furthermore, ΔHel1 MDA5 protein had reduced ATP hydrolysis compared with wild-type MDA5. Our results suggest that dampened MDA5 function delays T1D, yet loss of MDA5 promotes T1D.

Hepatitis B and Hepatitis D Viruses: A Comprehensive Update with an Immunological Focus.

Hepatitis B virus (HBV) and hepatitis delta virus (HDV) are highly prevalent viruses estimated to infect approximately 300 million people and 12-72 million people worldwide, respectively. HDV requires the HBV envelope to establish a successful infection. Concurrent infection with HBV and HDV can result in more severe disease outcomes than infection with HBV alone. These viruses can cause significant hepatic disease, including cirrhosis, fulminant hepatitis, and hepatocellular carcinoma, and represent a significant cause of global mortality. Therefore, a thorough understanding of these viruses and the immune response they generate is essential to enhance disease management. This review includes an overview of the HBV and HDV viruses, including life cycle, structure, natural course of infection, and histopathology. A discussion of the interplay between HDV RNA and HBV DNA during chronic infection is also included. It then discusses characteristics of the immune response with a focus on reactions to the antigenic hepatitis B surface antigen, including small, middle, and large surface antigens. This paper also reviews characteristics of the immune response to the hepatitis D antigen (including small and large antigens), the only protein expressed by hepatitis D. Lastly, we conclude with a discussion of recent therapeutic advances pertaining to these viruses.

Epstein-Barr Virus (EBV) Epithelial Associated Malignancies: Exploring Pathologies and Current Treatments.

Epstein-Barr virus (EBV) is one of eight known herpesviruses with the potential to infect humans. Globally, it is estimated that between 90-95% of the population has been infected with EBV. EBV is an oncogenic virus that has been strongly linked to various epithelial malignancies such as nasopharyngeal and gastric cancer. Recent evidence suggests a link between EBV and breast cancer. Additionally, there are other, rarer cancers with weaker evidence linking them to EBV. In this review, we discuss the currently known epithelial malignancies associated with EBV. Additionally, we discuss and establish which treatments and therapies are most recommended for each cancer associated with EBV.

Ginkgolic Acid Inhibits Herpes Simplex Virus Type 1 Skin Infection and Prevents Zosteriform Spread in Mice.

Herpes simplex virus type 1 (HSV-1) causes a lifelong latent infection with an estimated global prevalence of 66%. Primary and recurrent HSV infections are characterized by a tingling sensation, followed by an eruption of vesicles, which can cause painful erosions. Commonly used antiviral drugs against HSV infection are nucleoside analogues including acyclovir (ACV), famciclovir, and valacyclovir. Although these nucleoside analogues reduce morbidity and mortality in immunocompetent individuals, ACV-resistant HSV strains (ACVR-HSV) have been isolated from immunocompromised patients. Thus, ACVR-HSV infection poses a critical emerging public health concern. Recently, we reported that ginkgolic acid (GA) inhibits HSV-1 by disrupting viral structure, blocking fusion, and inhibiting viral protein synthesis. Additionally, we showed GA affords a broad spectrum of fusion inhibition of all three classes of fusion proteins, including those of HIV, Ebola, influenza A and Epstein Barr viruses. Here we report GA's antiviral activity against HSV-1 skin infection in BALB/cJ mice. GA-treated mice demonstrated a significantly reduced mortality rate and decreased infection scores compared to controls treated with dimethylsulfoxide (DMSO)-vehicle. Furthermore, GA efficiently inhibited ACVR-HSV-1 strain 17+ in vitro and in vivo. Since GA's mechanism of action includes virucidal activity and fusion inhibition, it is expected to work alone or synergistically with other anti-viral drugs, and we anticipate it to be effective against additional cutaneous and potentially systemic viral infections.

Author Correction: Ginkgolic acid inhibits fusion of enveloped viruses.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Ginkgolic acid inhibits fusion of enveloped viruses.

Ginkgolic acids (GA) are alkylphenol constituents of the leaves and fruits of Ginkgo biloba. GA has shown pleiotropic effects in vitro, including: antitumor effects through inhibition of lipogenesis; decreased expression of invasion associated proteins through AMPK activation; and potential rescue of amyloid-ß (Aß) induced synaptic impairment. GA was also reported to have activity against Escherichia coli and Staphylococcus aureus. Several mechanisms for this activity have been suggested including: SUMOylation inhibition; blocking formation of the E1-SUMO intermediate; inhibition of fatty acid synthase; non-specific SIRT inhibition; and activation of protein phosphatase type-2C. Here we report that GA inhibits Herpes simplex virus type 1 (HSV-1) by inhibition of both fusion and viral protein synthesis. Additionally, we report that GA inhibits human cytomegalovirus (HCMV) genome replication and Zika virus (ZIKV) infection of normal human astrocytes (NHA). We show a broad spectrum of fusion inhibition by GA of all three classes of fusion proteins including HIV, Ebola virus (EBOV), influenza A virus (IAV) and Epstein Barr virus (EBV). In addition, we show inhibition of a non-enveloped adenovirus. Our experiments suggest that GA inhibits virion entry by blocking the initial fusion event. Data showing inhibition of HSV-1 and CMV replication, when GA is administered post-infection, suggest a possible secondary mechanism targeting protein and DNA synthesis. Thus, in light of the strong effect of GA on viral infection, even after the infection begins, it may potentially be used to treat acute infections (e.g. Coronavirus, EBOV, ZIKV, IAV and measles), and also topically for the successful treatment of active lesions (e.g. HSV-1, HSV-2 and varicella-zoster virus (VZV)).