Herpes Simplex Virus Type 1 Keratitis Research Articles

Highly sensitive and naked-eye detection of herpes simplex virus type 1 using LAMP- CRISPR/Cas12 diagnostic technology and gold nanoparticles

Herpes simplex virus type 1 (HSV-1) Keratitis (HSK) is a highly prevalent eye disease worldwide, characterized by lifelong recurrent episodes and a major risk of leading to blindness. Detecting HSV-1 promptly and accurately can initiate a timely and appropriate therapeutic regimen, minimizing tissue damage and preventing vision impairment. Currently, PCR is the most reliable method for identifying HSV-1, but its utilization for point-of-care (POC) HSV-1 detection is limited due to the need for sophisticated equipment, particularly in areas with limited resources. Here, we propose a new method for on-site HSV detection by using LAMP-Cas12 diagnostic technology and gold nanoparticles. This technique possesses comparable sensitivity to qPCR, and its detection results could be easily read and interpreted without the need for complex equipment. In detecting HSV in clinical tear specimens, this strategy achieved a 93.9 % consistency in positive detection and a 100 % consistency in negative detection compared to qPCR. Our strategy innovates the technique of current HSV-1 detections and is expected to play a crucial role in POC diagnosis of HSK in the future.

Acyclovir Prophylaxis Predisposes to Antiviral-Resistant Recurrent Herpetic Keratitis

Long-term acyclovir (ACV) prophylaxis, recommended to prevent recurrent herpes simplex virus type 1 (HSV-1) ocular disorders, may pose a risk for ACV-refractory disease due to ACV resistance. We determined the effect of ACV prophylaxis on the prevalence of corneal ACV-resistant (ACV(R)) HSV-1 and clinical consequences thereof in patients with recurrent HSV-1 keratitis (rHK). Frequencies of ACV(R) viruses were determined in 169 corneal HSV-1 isolates from 78 rHK patients with a history of stromal disease. The isolates' ACV susceptibility profiles were correlated with clinical parameters to identify risk factors predisposing to ACV(R) rHK. Corneal HSV-1 isolates with >28% ACV(R) viruses were defined as ACV(R) isolates. Forty-four isolates (26%) were ACV-resistant. Multivariate analyses identified long-term ACV prophylaxis (≥12 months) (odds ratio [OR] 3.42; 95% confidence interval [CI], 1.32-8.87) and recurrence duration of ≥45 days (OR 2.23; 95% CI, 1.02-4.87), indicative of ACV-refractory disease, as independent risk factors for ACV(R) isolates. Moreover, a corneal ACV(R) isolate was a risk factor for ACV-refractory disease (OR 2.28; 95% CI, 1.06-4.89). The data suggest that long-term ACV prophylaxis predisposes to ACV-refractory disease due to the emergence of corneal ACV(R) HSV-1. ACV-susceptibility testing is warranted during follow-up of rHK patients.

The Kinetics of Herpes Virus on the Ocular Surface and Suppression of Its Reactivation

Herpes simplex virus type 1 (HSV-1) establishes a latent infection in sensory neurons that can sometimes be reactivated. HSV-1 keratitis often recurs and can be vision threatening. Reactivation of the latent virus can be stimulated by stress, immunosuppression, trauma, adrenergic iontophoresis, and UV radiation. Healthy and asymptomatic individuals are known to shed HSV-1, and this is a major factor in the spread of the virus. We investigated the frequency of shedding of HSV-1 DNA in tears of dry eye patients and individuals with conjunctivitis. Subjects were divided into 3 groups: normal (12 eyes), dry eye (11 eyes), and conjunctivitis (15 eyes). Quantitative real-time polymerase chain reaction was used for HSV DNA detection. The incidences of HSV positivity in the normal, dry eye, and conjunctivitis groups were 1 of 12 (8.3%), 3 of 11 (27.3%), and 4 of 15 (26.7%), respectively. We have previously shown that bromfenac sodium eye drops, intramuscular adenosine monophosphate, and geldanamycin effectively lower HSV-1 recurrence rates in a mouse model. Recently, we also found that nuclear factor κ-B, an IκB kinase-β inhibitor, could be a candidate for reducing HSV-1 reactivation. We sampled recipients' corneal buttons during keratoplasty and performed polymerase chain reaction. Cytomegalovirus (CMV) DNA was detected in corneas obtained from some patients, and the copy number of the detected CMV DNA was quantified. CMV DNA-positive samples were taken from 2 of the 3 patients with ocular pemphigoid; thus, in future work, the relationship between CMV in the cornea and the incidence/onset of ocular diseases of the anterior segment needs to be evaluated.

Herpes Simplex Virus-Induced Ocular Diseases: Detrimental Interaction Between Virus and Host

Herpes simplex virus type 1 (HSV-1) is a common cause of ocular diseases, affecting all parts of the visual axis. HSV-1 keratitis and uveitis represent two prevalent ocular diseases. The outcome of these potentially sightthreatening conditions depends on prompt diagnosis and treatment in order to counteract the detrimental intra-ocular virus-host interaction. This review recapitulates current insights on the diagnosis, pathogenesis, and treatment of HSV-1 keratitis and uveitis in patients and in the respective mouse models.

HPMPC, a Broad-Spectrum Topical Antiviral Agent, Inhibits Herpes Simplex Virus Type 1 Replication and Promotes Healing of Dendritic Keratitis in the New Zealand Rabbit Ocular Model

Previously, we demonstrated that HPMPC, a new, broad-spectrum antiviral agent, inhibited adenovirus type 5 in the New Zealand (NZ) rabbit ocular model (Cornea 1992; 11:529-33). Historically, no antiviral agent has been demonstrated to be effective against both herpes simplex virus type 1 (HSV-1) and adenovirus eye infections in an experimental animal model. In this study, we compared topical 0.2% HPMPC to 1% trifluridine and vehicle control in the NZ rabbit HSV-1 keratitis model. Using a double-masked, two-eye design, NZ rabbits were inoculated in both eyes with HSV-1 W strain (10(5) pfu/eye), and dendritic keratitis and HSV-1 ocular titers were measured serially. Compared with the control group, both topical 0.2% HPMPC and 1% trifluridine significantly reduced healing time of HSV-1 dendritic keratitis, lowered HSV-1 ocular titers on days 3 through 11, and shortened duration of HSV-1 shedding in the tear film. For all outcome parameters measured, topical 0.2% HPMPC was as effective as 1% trifluridine. A new concept of a broad-spectrum topical antiviral agent was shown to be effective against HSV-1 in an NZ rabbit keratitis model, and further development toward clinical application appears desirable.

Antiherpes Effect of Dextran Sulphate Combined with Acyclovir in vitro and in vivo

The combined antiviral effect of dextran sulphate (DS, MW 40000) and acyclovir (ACV) on herpes simplex virus type 1 (HSV-1) and Pseudorabies virus (PRV) in vitro and on experimental HSV-1 keratitis in rabbits, was studied. Dextran sulphate in combination with ACV results in synergistic effect, as measured by yield reduction assay and on herpes simplex keratitis in rabbits. The better therapeutic effect of the combination was proved by the decreased severity of ocular infection and the reduction of the virus shedding in tear film.

Potentiating effect of ribavirin on the anti-herpes activity of acyclovir

The combined antiviral effects of acyclovir (ACV) and ribavirin (Rbv) on herpes simplex virus type 1 (HSV-1) and pseudorabies virus (PRV) in cell cultures and on experimental HSV-1 keratitis in rabbits were studied. The antiviral activity in vitro was based on cytopathogenicity inhibition and yield reduction. The combination of the two drugs exhibited synergy as evaluated graphically (isobolograms). Rbv also potentiated the antiviral effect of ACV in vivo, in the experimental HSV-1 keratitis model in rabbits. This was evident from both the severity of corneal lesions and virus shedding in the tear film. The potentiating effect of Rbv on the anti-HSV-1 activity of ACV in vitro was reversed by guanosine.

Effects of phosphonylmethoxyalkyl-purine and -pyrimidine derivatives on TK + and TK − HSV-1 keratitis in rabbits

The phosphonylmethoxyalkyl derivatives HPMPA [( S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine], HPMPC [( S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] and PMEA [9-(2-phosphonylmethoxyethyl)adenine] were evaluated as 0.2% eyedrops for their efficacy in the treatment of experimental herpes simplex virus type 1 (HSV-1) keratitis in the rabbit model. BVDU 0.2% eyedrops were used as the reference treatment. HPMPA, HPMPC, PMEA and BVDU eyedrops showed a rapid and highly significant healing effect ( P < 0.005) on keratitis caused by TK + HSV-1 (McIntyre strain) when compared with placebo eyedrops, whereas BVDU treatment did not affect the course of TK − HSV-1 (VMW-1837) keratitis. HPMPA and HPMPC treatment again caused a highly significant healing ( P < 0.005, compared with placebo eyedrops). Although PMEA eyedrops were less effective than HPMPA or HPMPC eyedrops, the effect of PMEA eyedrops was significantly ( P < 0.05) different from the effect of either BVDU or placebo eyedrops.

Evaluation of ( E)-5-(2-bromovinyl)- and 5-vinyl-1-β-D-arabinofuranosyluracil (BrVaraU, VaraU) in the treatment of experimental herpes simplex virus type 1 keratitis in rabbits: Comparison with ( E)-5-(2-bromovinyl)-2′-deoxyuridine (BrVUdR)

The 5-substituted 1-β-D-arabinofuranosyl (araU) analogues, ( E)-5-(2-bromovinyl)-araU (BrVaraU) and 5-vinyl-araU (VaraU), which can be considered as structural analogues of ( E)-5-(2-bromovinyl)-2′-deoxyuridine (BrVUdR), are potent and selective inhibitors of herpes simplex virus type 1 (HSV-1) replication in vitro. BrVaraU and VaraU have been compared with BrVUdR for their therapeutic effect on acute HSV-1 keratitis in rabbits. Both araU derivatives applied as 0.1% eyedrops suppressed the development of keratitis as monitored by the reduced number of herpes efflorescences. The healing effect of BrVaraU and VaraU was less pronounced than that of 0.1% BrVUdR eyedrops, the difference between BrVUdR and VaraU being statistically significant at the 10th day of treatment. As a further indication of the healing effect the number of corneae with opacities seen after cessation of drug treatment were 3.3, 7.4, 27.6 and 46.9% for the BrVUdR-BrVaraU-, VaraU- and placebo-treated eyes, respectively.

Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines

Various 3-hydroxy-2-phosphonylmethoxypropyl (HPMP) and 2-phosphonylmethoxyethyl (PME) derivatives of purine [adenine (A), guanine (G), 2,6-diaminopurine (DAP), 2-monoaminopurine (MAP), hypoxanthine (HX)] and pyrimidine [cytosine (C), uracil (U), thymine (T)] have been evaluated for their antiviral properties. PMEDAP, (S)-HPMPA [and the cyclic phosphonate thereof, (S)-cHPMPA)], (S)-HPMPC, PMEG, PMEA, HPMPG and HPMPDAP proved to be effective inhibitors of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). (S)-HPMPA and (S)-cHPMPA were the most effective inhibitors of varicella-zoster virus (VZV), and (S)-HPMPC was the most effective inhibitor of cytomegalovirus (CMV). Against adenovirus (types 2, 3 and 4) and vaccinia virus again (S)-HPMPA and (S)-cHPMPA showed the greatest inhibitory activity. As a rule, the PME derivates were much less inhibitory to VZV, CMV, vaccinia and adenovirus than the HPMP derivatives. However, PMEA, PMEDAP and PMEMAP showed marked and selective activity against the human immunodeficiency virus (HIV). (S)-HPMPA was selected for further evaluation in animal model infections. It proved efficacious in the topical treatment of HSV-1 keratitis in rabbits and cutaneous HSV-1 infection in hairless mice, and in the systemic treatment of both HSV-1 and vaccinia virus infections in mice.

Experimental thymidine kinase-deficient HSV-1 keratitis: therapeutic attempts.

Trifluridine (TFT) and a structurally related analogue, 5-fluoro-2'-deoxyuridine (FDU), were investigated for their efficacy in the topical treatment of experimental keratitis caused by thymidine kinase-positive (TK+) and thymidine kinase-deficient (TK-) herpes simplex virus type 1 (HSV-1) strains. Bromovinyldeoxyuridine (BVDU) was used as a reference compound. Both 0.2% BVDU and 0.2% TFT eyedrops produced a highly significant healing of TK+HSV-1 keratitis as compared to the placebo and 0.2% FDU eyedrops (P much less than 0.005), whereas the latter compound did not differ from placebo eyedrops. In the treatment of TK HSV-1 keratitis, none of the drugs exhibited a beneficial healing effect, although the virus strain used was inhibited in vitro by TFT and FDU at a very low concentration (0.02-0.04 microgram/mL).

Efficacy of bromovinyldeoxyuridine in the treatment of herpes simplex virus and varicella-zoster virus eye infections

As has been established in rabbits, ( E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU) is superior to 5-iodo-2′-deoxyuridine (IDU) in the topical treatment of epithelial HSV-1 (herpes simplex virus type 1) keratitis, and superior to 5-trifluoromethyl-2′-deoxyuridine (TFT) in the topical treatment of deep stromal HSV-1 keratitis and HSV-1 uveitis. BVDU 0.1% eye drops have also proven efficacious in the treatment of patients with dendritic corneal ulcers, geographic corneal ulcers and stromal keratitis, and combined treatment of BVDU 0.1% eye drops with oral BVDU at 375 mg/day for 5 days led to a prompt healing of keratouveitis and skin lesions in patients with ophthalmic herpes zoster.

Herpes simplex acyclovir-resistant mutant in experimental keratouveitis.

Acyclovir is a potent and selective antiviral agent. Unfortunately, drug-resistant (acyclovir-resistant) mutants have already been reported in herpes simplex virus type 1 (HSV-1) orofacial infections. We have developed a laboratory acyclovir-resistant HSV-1 mutant. The natural course of acyclovir-resistant HSV-1 keratitis was found to be less virulent than that observed in wild type HSV-1 keratitis, but the rate of ganglionic latency was as high as that induced by the parental strain. In vitro studies and in vivo observation of rabbit corneas infected with acyclovir-resistant HSV-1 both demonstrated a significant sensitivity to vidarabine and bromovinyldeoxyuridine ([E]-5-[2-bromovinyl]-2'-deoxyuridine). The thymidine kinase activity of the acyclovir-resistant mutant was 69% of that of the wild type HSV-1.