Primary Herpes Simplex Virus Type Research Articles

Primary herpes simplex virus type 1 infection with acute liver failure in solid organ transplantation: Report of three cases and review

Herpes virus infections is not uncommon in solid organ transplantation patients. We report 3 cases with primary Herpes simplex virus type-1 (HSV1) infection with acute liver failure (ALF). This is a rare and potentially fatal entity that could be a donor-derived infection. Although the initial clinical presentation is non-specific, it should be considered as a differential diagnosis in HSV-negative serology patients with liver failure and empirical treatment must be started in combination with a drastic reduction of immunosuppression. A strategy of HSV prophylaxis for pre-transplant HSV seronegative patients must be stablished in order to reduce the risk of clinical disease.

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.

Comparison of the immunologic response to herpes simplex virus type 1 entry glycoproteins induced in humans after primary infection of oral or genital sites

<h3>Objectives</h3> We sought to determine potential differences in the humoral immune response to herpes simplex virus type 1 (HSV-1) in patients after primary infection in either oral or genital sites. <h3>Methods</h3> Serum samples from 20 patients with primary HSV-1 infection (10 oral, 10 genital) were compared. A neutralization assay categorized samples by their ability to inhibit virus entry into cells. An enzyme-linked immunosorbent assay determined the quantity of antibodies against each of the major HSV-1 glycoproteins (gD, gB, gC, gH/gL). Surface plasmon resonance imaging (SPRi) was used to estimate the quality of the response by determining the epitope specificity of antibodies against the receptor-binding glycoprotein gD. Information from these assays was combined to develop a comprehensive profile of immunologic response to HSV-1 infection. <h3>Results</h3> All 10 oral site serum samples contained significant levels of virus-specific antibodies to block virus entry and demonstrated excellent immune response to the major virion glycoproteins. In contrast, only 4 of the 10 genital site serum samples were able to block virus entry. The 6 genital site sera that failed to block entry had markedly reduced antiglycoprotein antibody levels, indicating a poor overall HSV-1 immunologic response. The quantity of antiglycoprotein antibodies in the 4 genital (protective) sera mirrored that induced by oral infection. Subsequently, SPRi was used to determine whether the qualitative response was equivalent between the oral and genital site sera. All 10 oral site sera targeted gD epitopes at levels significantly higher and more varied than those generated for the 4 protective genital site samples. Interestingly, the gD epitope profiles of the 6 nonprotective genital site samples were directed at a single non-neutralizing antigenic site on gD that is involved in cell-to-cell spread. <h3>Conclusions</h3> Based on a comprehensive profile of immunologic response to HSV-1 infection for individuals infected at either oral or genital sites, results of this study suggest that the site of primary infection is important in driving the overall humoral immune-protective response. Findings of this study will have direct implications for the future development of a glycoprotein-epitope–based HSV-1 vaccine.

Primary herpes simplex virus type 2 hepatitis diagnosed during laparoscopy

Primary herpes simplex virus type 2 hepatitis diagnosed during laparoscopy

Primary Herpes Simplex Virus Type 2 Infection Associated With Monoarthritis of the Knee

Abstract Monoarthritis associated with herpes virus infection is rare and previously only described in herpes simplex type 1, varicella zoster, and Epstein-Barr virus infections. Here, we report a case of monoarthritis of the knee associated with primary herpes simplex virus type 2 (HSV-2) infection in an immunocompetent 50-year-old woman. Herpes simplex virus type 2 DNA was detected in plasma and in the joint fluid. The patient had only mild symptoms of herpes simplex virus type 2, suggesting that virus-associated monoarthritis may be underrecognized and underreported.

Case 1: Peripheral Intravenous Catheter Site Swelling/Abscesses in the Neonate

1. Daniel Loeb, MD* 2. Jonathan J. Lee, MD† 3. Silvia Song, MD† 4. Arivarasan Karunamurthy, MD† 5. Robin P. Gehris, MD‡ 6. Sharmilarani H. Nanda, MD§ 1. *Department of Pediatrics and 2. ‡Department of Pediatric Dermatology, Department of Pediatric Teledermatology, and Department of Dermatology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA 3. †Department of Dermatology, University of Pittsburgh Medical Center, Pittsburgh, PA 4. §University of Pittsburgh Physicians, Pittsburgh, PA Pediatrics in Review came into being as I was beginning my pediatric training. The journal encouraged and educated me through a mostly US-based career as well as during a year in Europe and six years in central Africa. The educational content of Pediatrics in Review informed my care of tens of thousands of patients, and my first contribution to the journal was published in 1993. It has been a privilege to serve a ten-year term on the editorial board and to help guide the content of Index of Suspicion. This month, I turn 65. While I am not retiring, I am transitioning away from my editorial responsibilities with the journal. May each of you be as blessed as I have been by the career-enhancing education and encouragement offered by Pediatrics in Review ! Philip R. Fischer, MDAssociate Editor, Index of Suspicion An infant girl is born via cesarean delivery at 38 weeks’ gestation to a 21-year-old gravida 2, para 1 mother whose antenatal course is complicated by a recent primary vaginal herpes simplex virus (HSV) type 2 infection detected 5 days before the onset of labor. After cesarean delivery the baby briefly receives positive pressure ventilation via bag valve mask and has Apgar scores of 8 and 8 at 1 and 5 minutes, respectively. Her birthweight is 3,015 g. She requires continuous positive airway pressure for 2 days for respiratory distress. She is treated with ampicillin and gentamicin for 7 days for suspicion of clinical sepsis and with acyclovir for 10 days due to spontaneous rupture of membranes and the presence of active maternal genital …

HSV-2 Infection of Human Genital Epithelial Cells Upregulates TLR9 Expression Through the SP1/JNK Signaling Pathway.

It is known that herpes simplex virus type 2 (HSV-2) triggers the activation of Toll-like receptor (TLR) 9 signaling pathway and the consequent production of antiviral cytokines in dendritic cells. However, the impact of HSV-2 infection on TLR9 expression and signaling in genital epithelial cells, the primary HSV-2 targets, has yet to be determined. In the current study, by using both human genital epithelial cell lines and primary genital epithelial cells as models, we found that HSV-2 infection enhances TLR9 expression at both mRNA and protein levels. Such enhancement is virus replication-dependent and CpG-independent, while the HSV-2-mediated upregulation of TLR9 does not activate TLR9 signaling pathway. Mechanistically, a SP1 binding site on TLR9 promoter appears to be essential for HSV-2-induced TLR9 transactivation. Upon HSV-2 infection, SP1 translocates from the cytoplasm to the nucleus, and consequently binds to TLR9 promoter. By using specific inhibitors, the JNK signaling pathway is shown to be involved in the HSV-2-induced TLR9 transactivation, while HSV-2 infection increases the phosphorylation but not the total level of JNK. In agreement, antagonism of JNK signaling pathway inhibits the HSV-2-induced SP1 nuclear translocation. Taken together, our study demonstrates that HSV-2 infection of human genital epithelial cells promotes TLR9 expression through SP1/JNK signaling pathway. Findings in this study provide insights into HSV-2-host interactions and potential targets for immune intervention.

Acquired lymphangioma circumscriptum of the vulva secondary to severe herpes simplex infection

A 43-year-old woman presented to genito-urinary medicine with skin-coloured, papillomatous papules on the mons pubis and superior labia majora (figure 1). Routine sexually transmitted infection screening was normal. Given the...

Matrix-based controlled release delivery of acyclovir from poly-(ethylene co-vinyl acetate) rings

Up to 85% of the US adult population carries herpes simplex virus type-1 (HSV-1), with a smaller percentage (22%) infected with HSV-2. Herpesviruses can survive in lytic phase, when the viruses are actively replicating, or in latency, when the virus is functionally dormant in ganglia. Among drugs to treat these infections is acyclovir (ACV). ACV exhibits poor oral bioavailability and a short in vivo half-life; only about 10–15% of ingested drug enters the bloodstream and its half-life is about 3 h. With those disadvantages and the possibility of poor patient compliance, viral replication may not always be suppressed. To abrogate these shortcomings we propose local distribution via sustained drug release. We present a matrix-based antiherpetic ring, composed of poly(ethylene co-vinyl acetate), that releases ACV directly to the vaginal epithelium. A 30-day in vitro drug release trial showed that approximately 135 ± 20 μg/day of ACV was consistently released. Rings were nontoxic in cell culture and suppressed primary HSV-1 and HSV-2 replication. We expect these data form the basis for novel interventions in human health, where new prophylactics and therapeutics against genital herpes are truly needed.

Herpes Simplex Virus Type 2 Immediate Early Protein ICP27 Inhibits IFN-β Production in Mucosal Epithelial Cells by Antagonizing IRF3 Activation.

Herpes simplex virus type 2 (HSV-2) is the main cause of genital herpes and infections are common in the lower genital tract. Although neuronal and immune cells can be infected, epithelial cells, and keratinocytes are the primary HSV-2 target cells. HSV-2 establishes latency by evading the host immune system and its infection can also increase the risk of HIV-1 sexual transmission. Our pervious study found that HSV-2 immediate early protein ICP22, inhibited IFN-β production by interfering with the IRF3 pathway. However, ICP22-null HSV-2 did not completely lose the capability of suppressing IFN-β induction, suggesting the involvement of other viral components in the process. In this study, by using an ex vivo cervical explant model, we first demonstrated that HSV-2 can indeed inhibit IFN-β induction in human mucosal tissues. We further identified HSV-2 immediate early protein ICP27 as a potent IFN-β antagonist. ICP27 significantly suppresses the Sendai virus or polyinosinic-polycytidylic acid-induced IFN-β production in human mucosal epithelial cells, showing that ICP27 inhibits the IFN-β promoter activation, and IFN-β production at both mRNA and protein levels. Additional studies revealed that ICP27 directly associates with IRF3 and inhibits its phosphorylation and nuclear translocation, resulting in the inhibition of IFN-β induction. Our findings provide insights into the molecular mechanism underlying HSV-2 mucosal immune evasion, and information for the design of HSV-2 mucosal vaccines.

Host Vesicle Fusion Protein VAPB Contributes to the Nuclear Egress Stage of Herpes Simplex Virus Type-1 (HSV-1) Replication

The primary envelopment/de-envelopment of Herpes viruses during nuclear exit is poorly understood. In Herpes simplex virus type-1 (HSV-1), proteins pUL31 and pUL34 are critical, while pUS3 and some others contribute; however, efficient membrane fusion may require additional host proteins. We postulated that vesicle fusion proteins present in the nuclear envelope might facilitate primary envelopment and/or de-envelopment fusion with the outer nuclear membrane. Indeed, a subpopulation of vesicle-associated membrane protein-associated protein B (VAPB), a known vesicle trafficking protein, was present in the nuclear membrane co-locating with pUL34. VAPB knockdown significantly reduced both cell-associated and supernatant virus titers. Moreover, VAPB depletion reduced cytoplasmic accumulation of virus particles and increased levels of nuclear encapsidated viral DNA. These results suggest that VAPB is an important player in the exit of primary enveloped HSV-1 virions from the nucleus. Importantly, VAPB knockdown did not alter pUL34, calnexin or GM-130 localization during infection, arguing against an indirect effect of VAPB on cellular vesicles and trafficking. Immunogold-labelling electron microscopy confirmed VAPB presence in nuclear membranes and moreover associated with primary enveloped HSV-1 particles. These data suggest that VAPB could be a cellular component of a complex that facilitates UL31/UL34/US3-mediated HSV-1 nuclear egress.

Co-infection of Herpes Simplex Virus Type 2 and HIV Infections among Pregnant Women in Ibadan, Nigeria.

Introduction:Genital infection with herpes simplex virus type 2 (HSV-2) facilitates the acquisition of HIV, both mutually reinforcing infection. Lifelong latent HSV-2 infection raises concerns among women of reproductive age, considering the risk of neonatal transmission. In Nigeria, screening for HSV-2 and co-infection with HIV in antenatal clinics is not routine. This study was undertaken to determine the seroprevalence and co-infection of HSV-2 and HIV among pregnant women.Methods:This was a cross-sectional study conducted at the antenatal clinic of the University College Hospital, Ibadan, between March and August 2013. A total of 270 consenting pregnant women were enrolled. The study involved collecting socio-demographic data and laboratory determination of HSV-2 immunoglobulin G (IgG) and HIV seroprevalence using type-specific third-generation enzyme-linked immunosorbent assay (DIAPRO Diagnostic Bioprobes, Milan, Italy) and Uni-Gold Recombigen/ALERE determine, respectively. Data analyses were done using SPSS version 20 (SPSS Inc., IL, USA).Results:The seroprevalence for HSV-2 type-specific IgG was 33.3% (90/270), and HIV antibodies were identified in 19.63% (53/270) of the women. The HIV co-infection was 38.8% (35/90) among HSV-2-positive women and 10% (18/180) among HSV-2-negative women. Majority of the HSV-2 positive women (62.2%, 56/90) presented in their 2nd trimester while 18.9% (17/90) in their 3rd trimester.Conclusion:The seroprevalence of HSV-2 in this pregnant population is lower than what is observed in some other Sub-Saharan African countries; however, HSV-2/HIV co-infection is high. The HSV-2-seronegative women are still susceptible to primary HSV-2 infection in pregnancy with increased risk for HIV co-infection and neonatal transmission.

Modeling the pathology, immune responses, and kinetics of HSV-1 replication in the lip scarification model

The lip scarification model of herpes simplex virus type 1 (HSV-1) infection can be used to study acute infection in the orofacial tissue and the establishment of viral latency. In this study, mice were inoculated with HSV-1 and tissue harvested during the acute phase of infection. Clinical presentation of classical open sores on the lip of infected mice was observed. We defined the histopathology, disease scores, and immune infiltration of the lower lip during the formation and resolution of the clinical lesions. Finally, the kinetics of virus replication and transport of viral genomes to the trigeminal ganglia were established. With the virological and pathologic events of acute infection defined, the HSV-1 lip scarification model can now be used to study primary HSV-1 infection, invasion of the trigeminal ganglia, and establishment of latency.

Herpes simplex encephalitis is linked with selective mitochondrial damage; a post-mortem and in vitro study.

Herpes simplex virus type-1 (HSV-1) encephalitis (HSE) is the most commonly diagnosed cause of viral encephalitis in western countries. Despite antiviral treatment, HSE remains a devastating disease with high morbidity and mortality. Improved understanding of pathogenesis may lead to more effective therapies. Mitochondrial damage has been reported during HSV infection in vitro. However, whether it occurs in the human brain and whether this contributes to the pathogenesis has not been fully explored. Minocycline, an antibiotic, has been reported to protect mitochondria and limit brain damage. Minocycline has not been studied in HSV infection. In the first genome-wide transcriptomic study of post-mortem human HSE brain tissue, we demonstrated a highly preferential reduction in mitochondrial genome (MtDNA) encoded transcripts in HSE cases (n = 3) compared to controls (n = 5). Brain tissue exhibited a significant inverse correlation for immunostaining between cytochrome c oxidase subunit 1 (CO1), a MtDNA encoded enzyme subunit, and HSV-1; with lower abundance for mitochondrial protein in regions where HSV-1 was abundant. Preferential loss of mitochondrial function, among MtDNA encoded components, was confirmed using an in vitro primary human astrocyte HSV-1 infection model. Dysfunction of cytochrome c oxidase (CO), a mitochondrial enzyme composed predominantly of MtDNA encoded subunits, preceded that of succinate dehydrogenase (composed entirely of nuclear encoded subunits). Minocycline treated astrocytes exhibited higher CO1 transcript abundance, sustained CO activity and cell viability compared to non-treated astrocytes. Based on observations from HSE patient tissue, this study highlights mitochondrial damage as a critical and early event during HSV-1 infection. We demonstrate minocycline preserves mitochondrial function and cell viability during HSV-1 infection. Minocycline, and mitochondrial protection, offers a novel adjunctive therapeutic approach for limiting brain cell damage and potentially improving outcome among HSE patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1597-2) contains supplementary material, which is available to authorized users.

High prevalence of herpes simplex virus (HSV)- type 2 co-infection among HIV-positive women in Ukraine, but no increased HIV mother-to-child transmission risk.

BackgroundOver 3500 HIV-positive women give birth annually in Ukraine, a setting with high prevalence of sexually transmitted infections. Herpes simplex virus Type 2 (HSV-2) co-infection may increase HIV mother-to-child transmission (MTCT) risk. We explored factors associated with HSV-2 seropositivity among HIV-positive women in Ukraine, and its impact on HIV MTCT.MethodsData on 1513 HIV-positive women enrolled in the Ukraine European Collaborative Study from 2007 to 2012 were analysed. Poisson and logistic regression models respectively were fit to investigate factors associated with HSV-2 seropositivity and HIV MTCT.ResultsMedian maternal age was 27 years (IQR 24–31), 53 % (796/1513) had been diagnosed with HIV during their most recent pregnancy and 20 % had a history of injecting drugs. Median antenatal CD4 count was 430 cells/mm3 (IQR 290–580). Ninety-six percent had received antiretroviral therapy antenatally. HSV-2 seroprevalence was 68 % (1026/1513). In adjusted analyses, factors associated with HSV-2 antibodies were history of pregnancy termination (APR 1.30 (95 % CI 1.18–1.43) for ≥2 vs. 0), having an HIV-positive partner (APR 1.15 (95 % CI 1.05–1.26) vs partner’s HIV status unknown) and HCV seropositivity (APR 1.23 (95 % CI 1.13–1.35)). The overall HIV MTCT rate was 2.80 % (95 % CI 1.98–3.84); no increased HIV MTCT risk was detected among HSV-2 seropositive women after adjusting for known risk factors (AOR 1.43 (95 % CI 0.54–3.77).ConclusionNo increased risk of HIV MTCT was detected among the 68 % of HIV-positive women with antibodies to HSV-2, in this population with an overall HIV MTCT rate of 2.8 %. Markers of ongoing sexual risk among HIV-positive HSV-2 seronegative women indicate the importance of interventions to prevent primary HSV-2 infection during pregnancy in this high-risk group.

Genital Herpes Simplex Virus Type 1: Case Report of Oro-genital Infection by Autotransmission

Introduction: Herpes simplex virus type 1 (HSV-1) is most commonly transmitted during childhood via nonsexual contacts and is related to oral herpes, while herpes simplex virus type 2 (HSV-2) is usually transmitted through sexual contact and implies genital lesions. HSV-1, however, can also cause genital herpes. We present the unusual case of oral-genital spread of a primary HSV-1 infection in a young patient who had not initiated sexual activity. Case: A 13-year-old female patient presented to the emergency department for a painful lesion on the chin, suggestive of herpes infection. Topical acyclovir and oral antibiotic treatment were initiated. Forty-eight hours later she returned for intense vulvar pain associated with multiple vulvar ulcers and bilateral inguinal lymph nodes. PCR results for genital ulcer exudate and blood IgM were positive for HSV-1. As the patient had no history of sexual activity, the primary facial HSV-1 infection was considered most likely to have spread to the genital area via autotransmission. Discussion: Differential diagnosis of genital ulcers includes sexually transmitted diseases and non-infectious diseases. In the former group, the most common cause is HSV-2. Oro-genital spread of herpes infections through sexual contact as a route of transmission is not uncommon. The patient in the present report, however, denied having engaged in sexual activity of any type at any time. We thus consider that this unusual case highlights the autotransmission of an oral HSV-1 genital herpes infection to the genital area. Conclusion: The possibility of autotransmission of HSV-1 infection by skin contact from the facial region to the genital area can be overlooked. Prophylactic measures should be taken to avoid the spread of lesions to other locations, particularly the genital area.

Disseminated Primary Herpes Simplex Virus Type 2 Infection in a 22-Year-Old male.

We present a case of primary disseminated herpes simplex virus type 2 (HSV-2) cutaneous disease in a 22-year-old male. We discuss the immune response to HSV-2 infection as well as the extragenital manifestations of HSV-2 observed in immune-competent and immune-suppressed persons.

Primary Genital Herpes Simplex Virus Type I in Preterm Prelabour Rupture of Membranes at 30 Weeks' Gestation.

Background. Disseminated herpes simplex virus (HSV) in the neonate is associated with significant morbidity and mortality. Current guidelines recommend caesarean in third-trimester maternal primary genital HSV outbreaks to prevent transmission from mother to fetus. In the premature fetus, however, expectant management is often necessary to reduce morbidity of prematurity. The benefit of performing caesarean after 6 hrs of rupture of membranes (ROM) to reduce maternal-fetal transmission is unclear. Case. A female patient with primary genital HSV type 1 outbreak coinciding with preterm, prelabour rupture of membranes (PPROM) at 30 + 3 weeks' gestation. An immediate caesarean section was not performed after multidisciplinary team discussion due to the benefits of glucocorticoids on immune complications of prematurity. The patient had expectant management for 5 days with intravenous (IV) aciclovir and then delivered an infant vaginally with disseminated neonatal HSV. Conclusion. We address the rare presentation of primary HSV infection associated with PPROM and the dilemma of how to manage these patients given the limited literature. We discuss the role of intrauterine compartment monitoring with amniocentesis, the mode of delivery when ROM has occurred for 120 hours, expectant management to reduce prematurity, and the effectiveness of aciclovir to reduce viral shedding in the prevention of neonatal HSV.

Topical SMIP-7.7, a Toll–Like Receptor 7 Agonist, Protects against Genital Herpes Simplex Virus Type-2 Disease in the Guinea Pig Model of Genital Herpes

Development of more effective therapies for genital herpes simplex virus type-2 (HSV-2) infections remains a priority. The toll-like receptors (TLR) are attractive targets for the immunomodulation of primary and recurrent genital herpes infection. The guinea pig model of genital HSV-2 disease was therefore used to evaluate the efficacy of a new TLR-7 agonist, SMIP-7.7. The effects of SMIP-7.7 at concentrations between 0.90% and 0.09% were compared to the vehicle control or Aldara(®) (3M Health Care Limited, Northridge, CA, USA) as treatment for genital HSV-2 infections. Following intravaginal inoculation of Hartley guinea pigs with 10(6) pfu HSV-2 (MS strain), animals were treated intravaginally beginning at 36 h post-infection. Animals were evaluated for acute disease, acute virus replication, recurrent disease and shedding, as well as infection of the dorsal root ganglia. Treatment with SMIP-7.7 significantly decreased mean total lesion scores during primary infection (all doses, P<0.01 compared with vehicle control, and similar to Aldara(®)). Vaginal virus titres were reduced in treated animals compared with vehicle control (P<0.001 for each treatment versus vehicle control on day 4). Treatment with SMIP-7.7 also significantly decreased the number of recurrent lesion days, the number of days with recurrent virus shedding and the infection of the dorsal root ganglia compared to the vehicle control, and was similar to Aldara(®). As opposed to Aldara(®), SMIP-7.7 did not induce fever or weight loss during treatment. SMIP-7.7 improves the outcome of primary and recurrent HSV-2 disease comparable to Aldara(®) but without some of the side effects associated with Aldara(®).

Expression, Inducers and Cellular Sources of the Chemokine MIG (CXCL 9), During Primary Herpes Simplex Virus Type-1 Infection of the Cornea

Purpose: To investigate the production of monokine induced by gamma-interferon (MIG) during a primary Herpes simplex virus type 1 (HSV-1) infection of the cornea. We hypothesize that multiple CXCR3 ligands are involved in T cell recruitment during HSV-1 corneal infection and that neutrophils have the potential to contribute to their production.Materials and methods: Levels of MIG were evaluated in an in vivo murine model of HSV-1 corneal infection by quantitative ELISA. Cultured murine corneal fibroblast (MCF) cells and purified neutrophils were stimulated in vitro with IFN-γ and IL-1α to determine inducers of MIG. Cellular sources of MIG production in vivo were investigated via cellular depletion studies. Additionally, MIG production resulting from interaction between resident human corneal cells and neutrophils was evaluated in an ex vivo model of human corneal infection.Results: MIG was significantly elevated on days 2–6 and on day 8 following corneal infection. MCF and neutrophils secreted MIG in response to IFN-γ, but not IL-1α stimulation. Co-stimulation with IFN-γ and IL-1α induced a four-fold increase in MIG production by MCF. However, the same combination led to a three-fold decrease in MIG production by neutrophils. In vivo, a 52% reduction in MIG levels was observed in the neutrophil depleted host. In the human ex vivo model, MIG levels were significantly elevated in response to communication between HSV-1 infected corneal tissue and neutrophils.Conclusions: Here, we report the evidence for the production of MIG, a second CXCR3 ligand, during the primary immune response to HSV-1 corneal infection. Our results support the hypothesis that both neutrophils and resident corneal cells contribute to MIG production in vivo. However, neutrophils produce MIG in response to communication with HSV-1-infected resident corneal cells more efficiently than by direct interaction with virus. In addition, we found that MIG production by neutrophils and resident corneal cells was differentially regulated by IL-1α.