Application of Hydrogel Spacer SpaceOAR Vue for Prostate Radiotherapy.

Damage in the surrounding structures, including the rectum, due to unintended exposure to radiation is a large burden to bear for patients who undergo radiation therapy for prostate cancer. The use of injectable rectal spacers to distance the anterior rectum from the prostate is a potential strategy to reduce the dose of unintended radiation to the rectum. Hydrogel spacers are gaining increasing popularity in the treatment regimen for prostate cancer. After FDA approval of SpaceOAR, specialists are receiving an increasing number of referrals for hydrogel placements. In this paper, we review hydrogel spacers, the supporting clinical data, the best practices for hydrogel placement, and the risk of adverse events.

Disruption of innate defense responses by endoglycosidase HPSE promotes cell survival.

The drive to withstand environmental stresses and defend against invasion is a universal trait extant in all forms of life. While numerous canonical signaling cascades have been characterized in detail, it remains unclear how these pathways interface to generate coordinated responses to diverse stimuli. To dissect these connections, we followed heparanase (HPSE), a protein best known for its endoglycosidic activity at the extracellular matrix but recently recognized to drive various forms of late-stage disease through unknown mechanisms. Using herpes simplex virus-1 (HSV-1) infection as a model cellular perturbation, we demonstrate that HPSE acts beyond its established enzymatic role to restrict multiple forms of cell-intrinsic defense and facilitate host cell reprogramming by the invading pathogen. We reveal that cells devoid of HPSE are innately resistant to infection and counteract viral takeover through multiple amplified defense mechanisms. With a unique grasp of the fundamental processes of transcriptional regulation and cell death, HPSE represents a potent cellular intersection with broad therapeutic potential.

Heparanase-Regulated Syndecan-1 Shedding Facilitates Herpes Simplex Virus 1 Egress.

Herpes simplex virus 1 (HSV-1) can infect virtually all cell types in vitro An important reason lies in its ability to exploit heparan sulfate (HS) for attachment to cells. HS is a ubiquitous glycosaminoglycan located on the cell surface and tethered to proteoglycans such as syndecan-1. Previously, we have shown that heparanase (HPSE) facilitates the release of viral particles by cleaving HS. Here, we demonstrate that HPSE is a master regulator where, in addition to directly enabling viral release via HS removal, it also facilitates cleavage of HS-containing ectodomains of syndecan-1, thereby further enhancing HSV-1 egress from infected cells. Syndecan-1 cleavage is mediated by upregulation of matrix metalloproteases (MMPs) that accompanies higher HPSE expression in infected cells. By overexpressing HPSE, we have identified MMP-3 and MMP-7 as important sheddases of syndecan-1 shedding in corneal epithelial cells, which are natural targets of HSV-1 infection. MMP-3 and MMP-7 were also naturally upregulated during HSV-1 infection. Altogether, this paper shows a new connection between HSV-1 release and syndecan-1 shedding, a phenomenon that is regulated by HPSE and executed by the MMPs. Our results also identify new molecular markers for HSV-1 infection and new targets for future interventions.IMPORTANCE HSV-1 is a common cause of recurrent viral infections in humans. The virus can cause a range of mucosal pathologies. Efficient viral egress from infected cells is an important step for HSV-1 transmission and virus-associated pathologies. Host mechanisms that contribute to HSV-1 egress from infected cells are poorly understood. Syndecan-1 is a common heparan sulfate proteoglycan expressed by many natural target cells. Despite its known connection with heparanase, a recently identified mediator of HSV-1 release, syndecan-1 has not been previously investigated in HSV-1 release. In this study, we demonstrate that the shedding of syndecan-1 by MMP-3 and MMP-7 supports viral egress. We show that the mechanism behind the activation of these MMPs is mediated by heparanase, which is upregulated upon HSV-1 infection. Our study elucidates a new connection between HSV-1 egress, heparanase, and matrix metallopeptidases; identifies new molecular markers of infection; and provides potential new targets for therapeutic interventions.

An off-target effect of BX795 blocks herpes simplex virus type 1 infection of the eye.

Herpes simplex virus type 1 (HSV-1) causes recurrent mucocutaneous lesions in the eye that may advance to corneal blindness. Nucleoside analogs exemplified by acyclovir (ACV) form the primary class of antiherpetic drugs, but this class suffers limitations due to the emergence of viral resistance and other side effects. While studying the molecular basis of ocular HSV-1 infection, we observed that BX795, a commonly used inhibitor of TANK-binding kinase 1 (TBK1), strongly suppressed infection by multiple strains of HSV-1 in transformed and primary human cells, cultured human and animal corneas, and a murine model of ocular infection. Our investigations revealed that the antiviral activity of BX795 relies on targeting Akt phosphorylation in infected cells, leading to the blockage of viral protein synthesis. This small-molecule inhibitor, which was also effective against an ACV-resistant HSV-1 strain, shows promise as an alternative to existing drugs and as an effective topical therapy for ocular herpes infection. Collectively, our results obtained using multiple infection models and virus strains establish BX795 as a promising lead compound for broad-spectrum antiviral applications in humans.

Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1.

Herpes simplex virus-1 (HSV-1) causes lifelong recurrent pathologies without a cure. How infection by HSV-1 triggers disease processes, especially in the immune-privileged avascular human cornea, remains a major unresolved puzzle. It has been speculated that a cornea-resident molecule must tip the balance in favor of pro-inflammatory and pro-angiogenic conditions observed with herpetic, as well as non-herpetic, ailments of the cornea. Here, we demonstrate that heparanase (HPSE), a host enzyme, is the molecular trigger for multiple pathologies associated with HSV-1 infection. In human corneal epithelial cells, HSV-1 infection upregulates HPSE in a manner dependent on HSV-1 infected cell protein 34.5. HPSE then relocates to the nucleus to regulate cytokine production, inhibits wound closure, enhances viral spread, and thus generates a toxic local environment. Overall, our findings implicate activated HPSE as a driver of viral pathogenesis and call for further attention to this host protein in infection and other inflammatory disorders.

Zinc oxide tetrapods inhibit herpes simplex virus infection of cultured corneas.

PURPOSE: Infection of the human cornea by herpes simplex virus type-1 (HSV-1) can cause significant vision loss. The purpose of this study was to develop an ex vivo model to visualize viral growth and spread in the cornea. The model was also used to analyze cytokine production and study the antiviral effects of zinc oxide tetrapods. METHODS: A ß-galactosidase-expressing recombinant virus, HSV-1(KOS)tk12, was used to demonstrate the ability of the virus to enter and develop blue plaques on human corneal epithelial (HCE) cells and corneal tissues. Freshly obtained porcine corneas were cultured and then scratched before infection with HSV-1(KOS)tk12. The blue plaques on the corneas were imaged using a stereomicroscope. Western blot analysis for HSV-1 proteins was performed to verify HSV-1 infection of the cornea. Using the ex vivo model, zinc oxide tetrapods were tested for their anti-HSV-1 potential, and a cytokine profile was developed to assess the effects of the treatment. RESULTS: Cultured corneas and the use of ß-galactosidase-expressing HSV-1(KOS)tk12 virus can provide an attractive ex vivo model to visualize and study HSV-1 entry and spread of the infection in tissues. We found that unlike cultured HCE cells, which demonstrated nearly 100% infectivity, HSV-1 infection of the cultured cornea was more restrictive and took longer to develop. We also found that the zinc oxide tetrapod-shaped nano- and microstructures inhibited HSV infection of the cultured cells, as well as the cultured corneas. The cytokine profile of the infected samples was consistent with previous studies of HSV-1 corneal infection. CONCLUSIONS: The ability to visualize HSV-1 growth and spread in corneal tissues can provide new details about HSV-1 infection of the cornea and the efficacy of new cornea-specific antiviral drug candidates. The ex vivo model also demonstrates antiviral effects of zinc oxide tetrapods and adequately portrays the drug delivery issues that cornea-specific treatments face.

Intravaginal Zinc Oxide Tetrapod Nanoparticles as Novel Immunoprotective Agents against Genital Herpes.

Virtually all efforts to generate an effective protection against the life-long, recurrent genital infections caused by HSV-2 have failed. Apart from sexual transmission, the virus can also be transmitted from mothers to neonates, and it is a key facilitator of HIV coacquisition. In this article, we uncover a nanoimmunotherapy using specially designed zinc oxide tetrapod nanoparticles (ZOTEN) with engineered oxygen vacancies. We demonstrate that ZOTEN, when used intravaginally as a microbicide, is an effective suppressor of HSV-2 genital infection in female BALB/c mice. The strong HSV-2 trapping ability of ZOTEN significantly reduced the clinical signs of vaginal infection and effectively decreased animal mortality. In parallel, ZOTEN promoted the presentation of bound HSV-2 virions to mucosal APCs, enhancing T cell-mediated and Ab-mediated responses to the infection, and thereby suppressing a reinfection. We also found that ZOTEN exhibits strong adjuvant-like properties, which is highly comparable with alum, a commonly used adjuvant. Overall, to our knowledge, our study provides the very first evidence for the protective efficacy of an intravaginal microbicide/vaccine or microbivac platform against primary and secondary female genital herpes infections.

Heparanase is a host enzyme required for herpes simplex virus-1 release from cells.

Herpesviruses exemplified by herpes simplex virus-1 (HSV-1) attach to cell surface heparan sulfate (HS) for entry into host cells. However, during a productive infection, the HS moieties on parent cells can trap newly exiting viral progenies and inhibit their release. Here we demonstrate that a HS-degrading enzyme of the host, heparanase (HPSE), is upregulated through NF-kB and translocated to the cell surface upon HSV-1 infection for the removal of HS to facilitate viral release. We also find a significant increase in HPSE release in vivo during infection of murine corneas and that knockdown of HPSE in vivo inhibits virus shedding. Overall, we propose that HPSE acts as a molecular switch for turning a virus-permissive 'attachment mode' of host cells to a virus-deterring 'detachment mode'. Since many human viruses use HS as an attachment receptor, the HPSE-HS interplay may delineate a common mechanism for virus release.

Exploiting herpes simplex virus entry for novel therapeutics.

Herpes Simplex virus (HSV) is associated with a variety of diseases such as genital herpes and numerous ocular diseases. At the global level, high prevalence of individuals who are seropositive for HSV, combined with its inconspicuous infection, remains a cause for major concern. At the molecular level, HSV entry into a host cell involves multiple steps, primarily the interaction of viral glycoproteins with various cell surface receptors, many of which have alternate substitutes. The molecular complexity of the virus to enter a cell is also enhanced by the existence of different modes of viral entry. The availability of many entry receptors, along with a variety of entry mechanisms, has resulted in a virus that is capable of infecting virtually all cell types. While HSV uses a wide repertoire of viral and host factors in establishing infection, current therapeutics aimed against the virus are not as diversified. In this particular review, we will focus on the initial entry of the virus into the cell, while highlighting potential novel therapeutics that can control this process. Virus entry is a decisive step and effective therapeutics can translate to less virus replication, reduced cell death, and detrimental symptoms.