Herpes Simplex Virus Type 1 DNA Research Articles

Cytosolic DNA sensors activation of human astrocytes inhibits herpes simplex virus through IRF1 induction.

While astrocytes participate in the CNS innate immunity against herpes simplex virus type 1 (HSV-1) infection, they are the major target for the virus. Therefore, it is of importance to understand the interplay between the astrocyte-mediated immunity and HSV-1 infection. Both primary human astrocytes and the astrocyte line (U373) were used in this study. RT-qPCR and Western blot assay were used to measure IFNs, the antiviral IFN-stimulated genes (ISGs), IFN regulatory factors (IRFs) and HSV-1 DNA. IRF1 knockout or knockdown was performed with CRISPR/Cas9 and siRNA transfection techniques. Poly(dA:dT) could inhibit HSV-1 replication and induce IFN-β/IFN-λs production in human astrocytes. Poly(dA:dT) treatment of astrocytes also induced the expression of the antiviral ISGs (Viperin, ISG56 and MxA). Among IRFs members examined, poly(dA:dT) selectively unregulated IRF1 and IRF9, particularly IRF1 in human astrocytes. The inductive effects of poly(dA:dT) on IFNs and ISGs were diminished in the IRF1 knockout cells. In addition, IRF1 knockout attenuated poly(dA:dT)-mediated HSV-1 inhibition in the cells. The DNA sensors activation induces astrocyte intracellular innate immunity against HSV-1. Therefore, targeting the DNA sensors has potential for immune activation-based HSV-1 therapy.

A robust bioplatform based on DNA-gated nanoscale porous carbon derived from a metal-organic framework for specific detection of Herpes simplex virus type 1

In this study, a highly efficient sensing platform based on metal-organic framework-derived porous carbon (MOF-PC) and bio-gatekeeper strategy was designed for the sensitive detection of Herpes simplex virus type 1 (HSV-1). To realize the aim above, MOF-PC was obtained through the carbonization of the zeolitic imidazolate framework (ZIF-8). The electroactive dye methylene blue (MB) was then captured as a signal probe in the MOF-PC pores. Specifically, HSV-1 highly specific antisense ssDNA oligonucleotide was connected to MOF-PC through π-stacking interaction as a gatekeeper and sealed up the pores of MOF-PC. By adding the targets (synthetic ssDNA target or total genome HSV-1 DNA) and hybridization between the immobilized specific antisense ssDNA oligonucleotides and the targets, the double-stranded DNA (dsDNA) was separated from the MOF-PC surface due to the low affinity of the MOF-PC to the dsDNA. Meanwhile, MBs were released from the opened holes of MOF-PC. Therefore, the intensity of MB peak current in the absence of a target was high and then decreased by releasing and washing of MB molecules. The MB@MOF-PC responded linearly to synthetic ssDNA target in the range from 10−18 to 10−8 M and isolated total genome HSV-1 DNA in the range from 102 to 108 copies/mL. The detection limits of 0.79 aM and 83.4 copies/mL were obtained for the synthetic ssDNA target and total genome HSV-1 DNA, respectively.

Inhibitory effect on acute herpes and prevention of postherpetic neuralgia in herpes simplex virus-1-infected mice using Ricinus communis extract

Ricinus communis and valacyclovir (VACV) were tested for their effects on the progression of skin observation and pain responses in mice infected with herpes simplex virus type 1 (HSV-1). The mice were infected with HSV-1 and treated with R. communis (8, 16, or 48 mg/kg) or VACV (15, 45, or 90 mg/kg) twice daily from days 2 to 8 post-infection. Skin lesion development and pain-associated reactions were assessed 27 days after infection. HSV-1 infection resulted in zosteriform skin observation and increased pain-related scores. Both R. communis and VACV demonstrated a dose-dependent reduction in skin observation and pain-related ratings. The study also investigated the impact of the timing of R. communis and VACV administration on skin observation and pain responses and found that lesion scores were significantly reduced when R. communis treatment was initiated on day 2 post-infection. The inhibitory effects of R. communis and VACV on HSV-1 dissemination in the dorsal root ganglia were studied, showing a significant reduction in HSV-1 DNA replication number after the administration of both drugs. Additionally, the study aimed to investigate the impact of R. communis and VACV on the expression levels of pain-associated mRNA in the spinal cord of HSV-1-infected mice. The study demonstrated that R. communis therapy exhibited an inhibitory effect on pain-related factors.

Prevalence of Herpes Simplex and Varicella-Zoster Virus DNA in Corneal Grafts Is Higher than Expected.

(1) To determine the prevalence of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), varicella-zoster virus (VZV), and cytomegalovirus (CMV) DNA in donor corneas; (2) To evaluate the clinical outcome of the grafts with viral DNA and to compare donors with and without viral DNA. We analyzed data from all donors and recipients who underwent penetrating keratoplasty (PK) or Descemet membrane endothelial keratoplasty (DMEK) between September 2022 and March 2023. Donor corneoscleral rims and excised recipients' corneal buttons were tested for the presence of HSV-1, HSV-2, VZV, and CMV DNA by polymerase chain reaction (PCR). The results were known 2-3 days after the surgery. We closely followed up on patients whose grafts tested positive for viral DNA. We compared the medical histories of donors with and without viral DNA. We included 85 corneas from 67 donors. Seven (8.2%) donor corneas tested positive for HSV-1 (n = 3) or VZV (n = 4) DNA. We did not detect any HSV-2 or CMV DNA. In the postoperative follow-up of patients with positive PCR, a graft failure was observed in one and infections in two eyes. Re-operation was necessary in three of these cases (42.9%). Patients without herpes DNA in the donor cornea needed reoperation in 7.7% of the cases. Cultural duration, the cause of the donor's death, and the death-to-explantation interval did not differ significantly between donors with and without viral DNA. Additionally, 3 of the 7 (42.9%) donors with positive PCR were in a septic status at the time of death, compared to 21 of the 78 (26.9%) donors with negative PCR (p = 0.52). The prevalence of herpes DNA in the donor corneas was 8.2% and thus higher than previously reported. We did not notice any evidence for a donor-to-host transmission, but a higher rate of postoperative complications in recipients of the grafts with viral DNA. The donors with and without herpetic DNA did not differ significantly regarding systemic diagnoses or cultural conditions, but sepsis was more frequent in the group with viral DNA.

Proliferating cell nuclear antigen inhibitors block distinct stages of herpes simplex virus infection.

Proliferating cell nuclear antigen (PCNA) forms a homotrimer that encircles replicating DNA and is bound by DNA polymerases to add processivity to cellular DNA synthesis. In addition, PCNA acts as a scaffold to recruit DNA repair and chromatin remodeling proteins to replicating DNA via its interdomain connecting loop (IDCL). Despite encoding a DNA polymerase processivity factor UL42, it was previously found that PCNA associates with herpes simplex virus type 1 (HSV-1) replication forks and is necessary for productive HSV-1 infection. To define the role that PCNA plays during viral DNA replication or a replication-coupled process, we investigated the effects that two mechanistically distinct PCNA inhibitors, PCNA-I1 and T2AA, have on the HSV-1 infectious cycle. PCNA-I1 binds at the interface between PCNA monomers, stabilizes the homotrimer, and may interfere with protein-protein interactions. T2AA inhibits select protein-protein interactions within the PCNA IDCL. Here we demonstrate that PCNA-I1 treatment results in reduced HSV-1 DNA replication, late gene expression, and virus production, while T2AA treatment results in reduced late viral gene expression and infectious virus production. To pinpoint the mechanisms by which PCNA inhibitors affect viral processes and protein recruitment to replicated viral DNA, we performed accelerated native isolation of proteins on nascent DNA (aniPOND). Results indicate that T2AA inhibits recruitment of the viral uracil glycosylase UL2 and transcription regulatory factors to viral DNA, likely leading to a defect in viral base excision repair and the observed defect in late viral gene expression and infectious virus production. In addition, PCNA-I1 treatment results in decreased association of the viral DNA polymerase UL30 and known PCNA-interacting proteins with viral DNA, consistent with the observed block in viral DNA replication and subsequent processes. Together, we conclude that inhibitors of cellular PCNA block recruitment of key viral and cellular factors to viral DNA to inhibit viral DNA synthesis and coupled processes.

Novel Adjuvant S-540956 Targets Lymph Nodes and Reduces Genital Recurrences and Vaginal Shedding of HSV-2 DNA When Administered with HSV-2 Glycoprotein D as a Therapeutic Vaccine in Guinea Pigs.

Herpes simplex virus type 2 (HSV-2) is a leading cause of genital ulcer disease and a major risk factor for acquisition and transmission of HIV. Frequent recurrent genital lesions and concerns about transmitting infection to intimate partners affect the quality of life of infected individuals. Therapeutic vaccines are urgently needed to reduce the frequency of genital lesions and transmission. S-540956 is a novel vaccine adjuvant that contains CpG oligonucleotide ODN2006 annealed to its complementary sequence and conjugated to a lipid that targets the adjuvant to lymph nodes. Our primary goal was to compare S-540956 administered with HSV-2 glycoprotein D (gD2) with no treatment in a guinea pig model of recurrent genital herpes (studies 1 and 2). Our secondary goals were to compare S-540956 with oligonucleotide ODN2006 (study1) or glucopyranosyl lipid A in a stable oil-in-water nano-emulsion (GLA-SE) (study 2). gD2/S-540956 reduced the number of days with recurrent genital lesions by 56%, vaginal shedding of HSV-2 DNA by 49%, and both combined by 54% compared to PBS, and was more efficacious than the two other adjuvants. Our results indicate that S-540956 has great potential as an adjuvant for a therapeutic vaccine for genital herpes, and merits further evaluation with the addition of potent T cell immunogens.

Prevalence of Herpesvirus DNA in Corneal Transplant Recipients

Purpose: Graft failure after penetrating keratoplasty (PK) is a serious complication, especially in eyes with herpetic keratitis (HK). This study evaluated the prevalence and graft survival of herpes simplex virus type 1 (HSV-1) and varicella zoster virus (VZV) DNA in recipient corneas during PK. Methods: The retrospective study was performed at the Department of Ophthalmology at University Hospital in Mainz, Germany. We analyzed data from every patient who underwent PK between January 2020 and June 2021. According to our clinical routine, we performed HSV-1 and VZV polymerase chain reaction (PCR) on all excised corneal buttons regardless of the primary clinical diagnosis. Results: We included 112 eyes of 112 consecutive patients who underwent PK. At the time of PK, 91 (81.25%) patients had no history of HK and 21 (18.75%) patients did. The recipient corneas of 91 patients without a history of HK tested positive for HSV-1 DNA in 12 (13.2%) eyes, for VZV DNA in 3 (3.3%) eyes, and for HSV-1 and VZV DNA simultaneously in 2 (2.2%) eyes. The recipient corneas of 21 patients with a preoperative history of HK tested positive for HSV-1 DNA in 13 (61.9%) eyes and VZV DNA in 1 (4.8%) eye. All patients with positive herpes DNA and no history of HK prior to PK received antiherpetic treatment and had a 100% graft survival rate after 1 year. Conclusions: We found herpesvirus DNA in 18.7% of recipient corneas without clinical suspicion or history of herpes keratitis. This suggests the need of routine HSV-1 and VZV PCR testing in all explanted corneas regardless of clinical suspicion, to detect, treat and prevent possible recurrence of herpes infection in corneal grafts and support graft survival.

Identifying Cellular and Viral Factor Recruitment to Herpes Simplex Virus Type 1 Replication Forks

Herpes simplex virus type 1 (HSV‐1) is a ubiquitous pathogen that replicates the 152kbp viral genome within the nucleus of host cells. Replication of the HSV‐1 genome is catalyzed by viral replication machinery consisting of a DNA polymerase (UL30), processivity factor (UL42), helicase‐primase complex, origin binding protein (UL9), and a single stranded DNA binding protein. Despite encoding a viral DNA polymerase processivity factor, we found that host Proliferating Cell Nuclear Antigen (PCNA) interacts with HSV‐1 DNA at replication forks and associates with viral DNA in a replication‐dependent manner. PCNA is a homotrimer that provides processivity to cellular DNA polymerases and selectively recruits DNA damage response and DNA repair factors to cellular replication forks. We therefore hypothesized that PCNA associates at viral replication forks to promote HSV‐1 replication while also tethering cellular DNA repair proteins to replicating viral DNA. To test this, we used two models to identify how associated factors change as a function of PCNA: a known PCNA inhibitor, PCNA‐I1, and a cell line that was engineered to inducibly express a shRNA targeting PCNA. We performed a technique adapted from isolation of proteins on nascent DNA (iPOND) to isolate HSV‐1 DNA from infected cells and identified associated viral and cellular proteins. Cells were infected and replicating viral DNA was selectively labeled with EdC. Labeled DNA was specifically and irreversibly tagged via the covalent attachment of biotin azide via click reaction. Biotin‐tagged DNA was purified on streptavidin‐coated beads and associated proteins were eluted and identified by mass spectrometry. As a complimentary approach, we also performed immunofluorescence (IF) to confirm iPOND data. We found that PCNA is associated with viral DNA despite treatment with PCNA‐I1, an observation that is consistent with IF imaging data. Viral replication proteins UL30, UL42, and UL9 decreased in the presence of PCNA‐I1. DNA damage response proteins such as mismatch repair proteins and RECQL both decreased up to 10‐fold. Of note, however, proteins that make up the MRN complex, a class of proteins that functions in DNA break repair, restart of stalled replication forks, and viral DNA infection, increased in response to PCNA‐I1 treatment. Given this data, PCNA may be involved in tethering viral replication proteins, cellular DNA repair proteins, and/or virion assembly proteins to viral replication forks.

Preventing neonatal herpes: Protection after maternal mRNA-lipid nanoparticle vaccination equals or exceeds that from prior maternal genital infection in murine models

Abstract Neonates are vulnerable to poor outcomes from herpes simplex virus (HSV), but maternal infection eliciting non-sterilizing immunity prior to delivery provides some protection. We are therefore pursuing birthing parent vaccination with nucleoside-modified mRNA-lipid nanoparticles (mRNA-LNPs) to prevent neonatal herpes. Our trivalent vaccine encodes HSV type 2 (HSV-2) proteins involved in attachment and immune evasion (gC2, gD2, and gE2). We have shown that this vaccine protects against genital HSV and neonatal HSV-2 in mice. Here, we tested how well murine dam vaccination prior to pregnancy protects pups against HSV type 1 (HSV-1) challenge compared to prior maternal intravaginal HSV-1 infection. Dams were immunized intramuscularly with the HSV-2 trivalent mRNA-LNP vaccine or a control immunogen (PolyC RNA-LNP), or were infected intravaginally with HSV-1 (HSV-1 ivag). Pups were challenged intranasally with HSV-1 on the 3rd day of life. Pups born to dams previously immunized or infected survived through 28 days (mRNA 95% vs. HSV-1 ivag 96%, N.S.; vs. PolyC 13%, p<0.0001). Likewise, they were protected from HSV-1 dissemination to the brain, lung, liver, spleen, and kidney by plaque assay (mRNA 2/45 organs affected vs. HSV-1 ivag 6/20, p=0.0083; vs. PolyC 69/80, p<0.0001). Additionally, fewer organs showed necrosis by histopathology of brain, lung, and liver, though not statistically significant, and fewer mRNA and HSV-1 ivag pups had detectable HSV-1 DNA in the trigeminal ganglia by qPCR (mRNA 6/30 vs. HSV-1 ivag 7/26, N.S.; vs. PolyC 17/18, p<0.0001). These studies demonstrate that the mRNA vaccine provides comparable to improved protection against neonatal HSV-1 challenge versus prior maternal HSV-1 intravaginal infection. AD was supported by NIH NIAID T32 AI118684. HMF, SA, GHC, and DW were supported by NIH NIAID R01 AI139618 and an unrestricted grant from BioNTech SE. KPE was supported by NIH T32 NS007180. The funders had no input or influence on the content of this abstract.

Complete Genome Sequence of Herpes Simplex Virus 2 Strain G.

Herpes simplex virus type 2 (HSV-2) is a common causative agent of genital tract infections. Moreover, HSV-2 and HIV infection can mutually increase the risk of acquiring another virus infection. Due to the high GC content and highly repetitive regions in HSV-2 genomes, only the genomes of four strains have been completely sequenced (HG52, 333, SD90e, and MS). Strain G is commonly used for HSV-2 research, but only a partial genome sequence has been assembled with Illumina sequencing reads. In the current study, we de novo assembled and annotated the complete genome of strain G using PacBio long sequencing reads, which can span the repetitive regions, analyzed the ‘α’ sequence, which plays key roles in HSV-2 genome circulation, replication, cleavage, and packaging of progeny viral DNA, identified the packaging signals homologous to HSV-1 within the ‘α’ sequence, and determined both termini of the linear genome and cleavage site for the process of concatemeric HSV-2 DNA produced via rolling-circle replication. In addition, using Oxford Nanopore Technology sequencing reads, we visualized four HSV-2 genome isomers at the nucleotide level for the first time. Furthermore, the coding sequences of HSV-2 strain G have been compared with those of HG52, 333, and MS. Moreover, phylogenetic analysis of strain G and other diverse HSV-2 strains has been conducted to determine their evolutionary relationship. The results will aid clinical research and treatment development of HSV-2.

Molecular Detection of HSV type 2 Infection among Infertile Males in Khartoum State, Sudan

Background: Herpes simplex virus (HSV) infections of humans were first documented in ancient Greece. HSVs belong to family Herpesviridae, and are characterized by being enveloped, double-stranded DNA viruses with relatively large complex genomes. Herpes simplex virus type 2 (HSV-2) DNA seems to play a significant role in male infertility, it is significantly related to low sperm count as well as poor motility.
 Aim: This study aimed to determine the incidence of HSV-2 DNA among infertile males in Khartoum State, Sudan by using molecular methods.
 Methods: The study was carried out in Khartoum State, Sudan, during May-August 2018. A total of 50 semen samples from infertile males were included. HSV-2 was detected using real-time polymerase chain reaction (RT-PCR).
 Result: Among 50 semen samples from infertile males, 6(12%) samples were found positive for HSV-2 DNA.
 Conclusion: Our findings showed no association between HSV-2 DNA and low sperm count in infertile Sudanese men. Our study also revealed the need for further investigations in different parts of the country to highlight the extent of the viral related men infertility problem in Sudan.
 Keywords: HSV-2, RT-PCR, infertility, men, Sudan

HSV-1 DNA Replication-Coordinated Regulation by Viral and Cellular Factors.

DNA replication is an integral step in the herpes simplex virus type 1 (HSV-1) life cycle that is coordinated with the cellular DNA damage response, repair and recombination of the viral genome, and viral gene transcription. HSV-1 encodes its own DNA replication machinery, including an origin binding protein (UL9), single-stranded DNA binding protein (ICP8), DNA polymerase (UL30), processivity factor (UL42), and a helicase/primase complex (UL5/UL8/UL52). In addition, HSV-1 utilizes a combination of accessory viral and cellular factors to coordinate viral DNA replication with other viral and cellular processes. The purpose of this review is to outline the roles of viral and cellular proteins in HSV-1 DNA replication and replication-coupled processes, and to highlight how HSV-1 may modify and adapt cellular proteins to facilitate productive infection.

Primary HSV-2 Infection in Early Pregnancy Results in Transplacental Viral Transmission and Dose-Dependent Adverse Pregnancy Outcomes in a Novel Mouse Model.

Herpes simplex virus type 2 (HSV-2) infection affects 24 million births annually and is associated with adverse pregnancy outcomes, including neonatal herpes; however, the mechanisms underlying in utero transmission of HSV-2 are largely unknown. We examined the effects of primary HSV-2 infection during early pregnancy on gestational outcomes in a novel, clinically relevant mouse model. Pregnant C57BL/6 mice were infected intravaginally with 102–105 pfu/mL HSV-2 on gestation day (gd) 4.5. Controls were infected, nonpregnant, diestrus-staged mice and pregnant, uninfected mice. Compared to nonpregnant mice, pregnant mice were 100-fold more susceptible to HSV-2 infection. Three days post-inoculation (gd7.5), viral DNA was present in implantation sites, but pregnancy outcomes were largely unaffected by infection. Eight days post-inoculation (gd12.5), HSV-2 DNA persisted in placental tissues, resulting in inflammation and hemorrhage. Fetal and placental weights were reduced and fetal loss was observed with high viral doses. HSV-2 DNA and increased expression of pro-inflammatory mediators were detected in fetal tissues at gd12.5, signifying viral transmission and fetal infection, even with low viral doses. This mouse model shows a dose-dependent effect of primary HSV-2 infection on pregnancy outcomes and suggests that fetal loss may occur due to placental inflammation, thus providing valuable insight into in utero transmission of HSV-2.

Cluster of Symptomatic Graft-to-Host Transmission of Herpes Simplex Virus Type 1 in an Endothelial Keratoplasty Setting

PurposeDescemet's membrane endothelial keratoplasty (DMEK) is becoming the gold standard to treat corneal endothelial dysfunctions worldwide. Compared with conventional penetrating keratoplasty, infectious complications after DMEK are ill defined. We describe the clinical picture of 2 DMEK recipients, operated on the same day and in the same clinic, who developed atypical herpes simplex virus type 1 (HSV-1) infection in the transplant recipient eye within days post-DMEK. Because recipients received cornea tissue from 2 different donors prepared by the same eye bank, the likelihood of a common HSV-1 source was determined.DesignCase series.ParticipantsTwo DMEK recipients who developed atypical intraocular HSV-1 disease shortly after surgery and surplus cornea specimens of 6 donors.MethodsSurplus cornea donor (pre-DMEK cornea remnants and conditioned cornea storage and transport media) and recipient samples (post-DMEK aqueous humor) were assayed for HSV-1 DNA and infectious virus by real-time polymerase chain reaction (RT-PCR) and cell culture, respectively. Target-enriched whole viral genome sequencing was performed on HSV-1 DNA–positive ocular specimens.Main Outcome MeasuresClinical picture of atypical intraocular HSV-1 infection post-DMEK and presence and homology of HSV-1 genomes between ocular specimens of DMEK donors and recipients.ResultsHerpes simplex virus type 1 DNA was detected in aqueous humor and donor cornea specimens of both DMEK cases, but not in the cornea remnants of 6 randomly selected donors processed by the same eye bank. Infectious HSV-1 was isolated from the cornea remnant and corresponding culture medium of 1 cornea donor. Notably, whole-genome sequencing of virus DNA-positive specimens demonstrated exceptionally high genetic similarity between HSV-1 strains in recipient and donor specimens of both DMEK cases.ConclusionsData indicate cross-contamination of cornea grafts during DMEK preparation with subsequent graft-to-host HSV-1 transmission that caused atypical sight-threatening herpetic eye disease shortly after DMEK. Ophthalmologists should be aware that HSV-1 transmission by DMEK is possible and can lead to atypical ocular disease, a condition that can easily be prevented by taking appropriate technical and clinical measures at both eye bank and surgical levels.

Polluted Air Exposure Compromises Corneal Immunity and Exacerbates Inflammation in Acute Herpes Simplex Keratitis.

Air pollution is a serious environmental issue worldwide in developing countries’ megacities, affecting the population’s health, including the ocular surface, by predisposing or exacerbating other ocular diseases. Herpes simplex keratitis (HSK) is caused by the herpes simplex virus type 1 (HSV-1). The primary or recurring infection in the ocular site causes progressive corneal scarring that may result in visual impairment. The present study was designed to study the immunopathological changes of acute HSK under urban polluted air, using the acute HSK model combined with an experimental urban polluted air exposure from Buenos Aires City. We evaluated the corneal clinical outcomes, viral DNA and pro-inflammatory cytokines by RT-PCR and ELISA assays, respectively. Then, we determined the innate and adaptive immune responses in both cornea and local lymph nodes after HSV-1 corneal by immunofluorescence staining and flow cytometry. Our results showed that mice exposed to polluted air develop a severe form of HSK with increased corneal opacity, neovascularization, HSV-1 DNA and production of TNF-α, IL-1β, IFN-γ, and CCL2. A high number of corneal resident immune cells, including activated dendritic cells, was observed in mice exposed to polluted air; with a further significant influx of bone marrow-derived cells including GR1+ cells (neutrophils and inflammatory monocytes), CD11c+ cells (dendritic cells), and CD3+ (T cells) during acute corneal HSK. Moreover, mice exposed to polluted air showed a predominant Th1 type T cell response over Tregs in local lymph nodes during acute HSK with decreased corneal Tregs. These findings provide strong evidence that urban polluted air might trigger a local imbalance of innate and adaptive immune responses that exacerbate HSK severity. Taking this study into account, urban air pollution should be considered a key factor in developing ocular inflammatory diseases.

Independent and Correlated Role of Apolipoprotein E ɛ4 Genotype and Herpes Simplex Virus Type 1 in Alzheimer's Disease.

The ɛ4 allele of the Apolipoprotein E (APOE) gene in individuals infected by Herpes simplex virus type 1 (HSV-1) has been demonstrated to be a risk factor in Alzheimer's disease (AD). APOE-ɛ4 reduces the levels of neuronal cholesterol, interferes with the transportation of cholesterol, impairs repair of synapses, decreases the clearance of neurotoxic peptide amyloid-β (Aβ), and promotes the deposition of amyloid plaque, and eventually may cause development of AD. HSV-1 enters host cells and can infect the olfactory system, trigeminal ganglia, entorhinal cortex, and hippocampus, and may cause AD-like pathological changes. The lifecycle of HSV-1 goes through a long latent phase. HSV-1 induces neurotropic cytokine expression with pro-inflammatory action and inhibits antiviral cytokine production in AD. It should be noted that interferons display antiviral activity in HSV-1-infected AD patients. Reactivated HSV-1 is associated with infectious burden in cognitive decline and AD. Finally, HSV-1 DNA has been confirmed as present in human brains and is associated with APOEɛ4 in AD. HSV-1 and APOEɛ4 increase the risk of AD and relate to abnormal autophagy, higher concentrations of HSV-1 DNA in AD, and formation of Aβ plaques and neurofibrillary tangles.

Prevalence of active infection by herpes simplex virus type 2 in patients with high-risk human papillomavirus infection: A cross-sectional study.

The aim is to determine the prevalence of active infection by herpes simplex virus type 2 (HSV-2) among Mexican women with high-risk human papillomavirus (HR-HPV) cervical infection, recruited from public gynecology and colposcopy services. In a cross-sectional study, HSV-2 antibodies, HSV-2 DNA, and HR-HPV DNA were quantified. Significant differences in HSV-2 seroprevalence and HSV-2 active infection rates were found between negative and positive HR-HPV cases. HSV-2 seroprevalence was 28.15% and 16.1% (P = .0001), while HSV-2 active infection rates were 6.83% and 0.62% (P = .001) for positive and negative HR-HPV groups, respectively. The risk of HSV-2 seropositivity was 1.7 times greater for HR-HPV-positive cases (P = .02). Similarly, HR-HPV-positive cases were nine times more likely to have an HSV-2 active infection than HR-HPV-negative cases (P = .03). High HSV-2/h-HPV coinfection rates were observed among women recruited from public gynecology and colposcopy services. The main factors related to an HSV-2 active infection are a history of risky sexual behavior and HR-HPV infection. The prevalence of HSV-2 active infection among positive HR-HPV subjects indicate that these infections constitute an important group of STIs in Mexico.

The presence and impact of herpes virus DNA in recipient cornea and aqueous humor on graft survival following penetrating keratoplasty

Reactivation of herpes viruses poses threat to corneal graft survival. This study evaluated the presence of herpes simplex virus type 1 (HSV-1), HSV type 2 (HSV-2), and cytomegalovirus (CMV) DNA in recipient corneas and the aqueous humor of patients undergoing penetrating keratoplasty (PKP), and the impact on graft survival. This retrospective study reviewed 90 eyes of 71 patients underwent PKP between 2008 and 2016. Cornea and aqueous humor samples were sent for polymerase chain reaction (PCR) testing for viral DNA. The main outcomes were PCR results and graft survival. Recipient corneas tested positive for HSV-1 in 47 eyes (52.2%), for HSV-2 in 24 eyes (26.7%), and for CMV in seven eyes (7.8%). Aqueous humor tested positive for HSV-1 in 44 eyes (48.9%), for HSV-2 in 25 eyes (27.8%), and for CMV in eight eyes (8.9%). The presence of aqueous HSV-1 DNA was associated with higher risk of graft failure (p=0.005), whereas corneal HSV-1 DNA was not. The presence of HSV-2 DNA had no significant impact on graft survival. Aqueous CMV DNA was associated with higher risk of graft failure in univariate model, but not in multivariate model. There were high positive rates of HSV-1, HSV-2, and CMV DNA in recipient corneas and aqueous humor at the time of PKP, even among patients not suspected of latent viral infection. The presence of aqueous HSV-1 DNA was associated with higher risk of graft failure.

HSV-2 Cellular Programming Enables Productive HIV Infection in Dendritic Cells.

Genital herpes is a common sexually transmitted infection caused by herpes simplex virus type 2 (HSV-2). Genital herpes significantly enhances the acquisition and transmission of HIV-1 by creating a microenvironment that supports HIV infection in the host. Dendritic cells (DCs) represent one of the first innate cell types that encounter HIV-1 and HSV-2 in the genital mucosa. HSV-2 infection has been shown to modulate DCs, rendering them more receptive to HIV infection. Here, we investigated the potential mechanisms underlying HSV-2-mediated augmentation of HIV-1 infection. We demonstrated that the presence of HSV-2 enhanced productive HIV-1 infection of DCs and boosted inflammatory and antiviral responses. The HSV-2 augmented HIV-1 infection required intact HSV-2 DNA, but not active HSV-2 DNA replication. Furthermore, the augmented HIV infection of DCs involved the cGAS-STING pathway. Interestingly, we could not see any involvement of TLR2 or TLR3 nor suppression of infection by IFN-β production. The conditioning by HSV-2 in dual exposed DCs decreased protein expression of IFI16, cGAS, STING, and TBK1, which is associated with signaling through the STING pathway. Dual exposure to HSV-2 and HIV-1 gave decreased levels of several HIV-1 restriction factors, especially SAMHD1, TREX1, and APOBEC3G. Activation of the STING pathway in DCs by exposure to both HSV-2 and HIV-1 most likely led to the proteolytic degradation of the HIV-1 restriction factors SAMHD1, TREX1, and APOBEC3G, which should release their normal restriction of HIV infection in DCs. This released their normal restriction of HIV infection in DCs. We showed that HSV-2 reprogramming of cellular signaling pathways and protein expression levels in the DCs provided a setting where HIV-1 can establish a higher productive infection in the DCs. In conclusion, HSV-2 reprogramming opens up DCs for HIV-1 infection and creates a microenvironment favoring HIV-1 transmission.

Psoromic Acid, a Lichen-Derived Molecule, Inhibits the Replication of HSV-1 and HSV-2, and Inactivates HSV-1 DNA Polymerase: Shedding Light on Antiherpetic Properties.

Psoromic acid (PA), a bioactive lichen-derived compound, was investigated for its inhibitory properties against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), along with the inhibitory effect on HSV-1 DNA polymerase, which is a key enzyme that plays an essential role in HSV-1 replication cycle. PA was found to notably inhibit HSV-1 replication (50% inhibitory concentration (IC50): 1.9 μM; selectivity index (SI): 163.2) compared with the standard drug acyclovir (ACV) (IC50: 2.6 μM; SI: 119.2). The combination of PA with ACV has led to potent inhibitory activity against HSV-1 replication (IC50: 1.1 µM; SI: 281.8) compared with that of ACV. Moreover, PA displayed equivalent inhibitory action against HSV-2 replication (50% effective concentration (EC50): 2.7 μM; SI: 114.8) compared with that of ACV (EC50: 2.8 μM; SI: 110.7). The inhibition potency of PA in combination with ACV against HSV-2 replication was also detected (EC50: 1.8 µM; SI: 172.2). Further, PA was observed to effectively inhibit HSV-1 DNA polymerase (as a non-nucleoside inhibitor) with respect to dTTP incorporation in a competitive inhibition mode (half maximal inhibitory concentration (IC50): 0.7 μM; inhibition constant (Ki): 0.3 μM) compared with reference drugs aphidicolin (IC50: 0.8 μM; Ki: 0.4 μM) and ACV triphosphate (ACV-TP) (IC50: 0.9 μM; Ki: 0.5 μM). It is noteworthy that the mechanism by which PA-induced anti-HSV-1 activity was related to its inhibitory action against HSV-1 DNA polymerase. Furthermore, the outcomes of in vitro experiments were authenticated using molecular docking analyses, as the molecular interactions of PA with the active sites of HSV-1 DNA polymerase and HSV-2 protease (an essential enzyme required for HSV-2 replication) were revealed. Since this is a first report on the above-mentioned properties, we can conclude that PA might be a future drug for the treatment of HSV infections as well as a promising lead molecule for further anti-HSV drug design.