Toll-like receptors as novel therapeutic targets for herpes simplex virus infection.

Seropositivity for HSV reaches more than 70% within the world population, and yet no approved vaccine exists. While HSV1 is responsible for keratitis, encephalitis, and labialis, HSV2 carriers have a high susceptibility to other STD infections, such as HIV. Induction of antiviral innate immune responses upon infection depends on a family of pattern recognition receptors called Toll-like receptors (TLR). TLRs bridge innate and adaptive immunity by sensing virus infection and activating antiviral immune responses. HSV adopts smart tricks to evade innate immunity and can also manipulate TLR signaling to evade the immune system or even confer destructive effects in favor of virus replication. Here, we review mechanisms by which HSV can trick TLR signaling to impair innate immunity. Then, we analyze the role of HSV-mediated molecular cues, in particular, NF-κB signaling, in promoting protective versus destructive effects of TLRs. Finally, TLR-based therapeutic opportunities with the goal of preventing or treating HSV infection will be discussed.

Eye Complications During Dupilumab Treatment for Severe Atopic Dermatitis.

Dupilumab, the first biologic approved for treatment of atopic dermatitis, has demonstrated significant clinical effect and quality of life-enhancing capacity in clinical trials. In these, dupilumab-associated conjunctivitis where reported in a minority of patients. The present case series describe 10 patients treated with dupilumab where eye complications were very common. We have described patient characteristics, including FLG mutations, atopic history and clinical effect of dupilumab. Nine of 10 developed eye-complications, most commonly conjunctivitis (in 7/10). Other adverse events were herpes simplex virus uveitis and varicella-zoster virus meningitis. Although our case series is small, we conclude that dupilumab is an effective treatment option in severe atopic dermatitis, but that the risk of adverse events from the eyes and recurrence of herpes virus infections should be kept in mind. Close collaboration with an ophthalmologist is recommended, especially among patients with severe, long-lasting atopic dermatitis and/or previous eye disease.

Interferon epsilon in the reproductive tract of healthy and genital herpes simplex virus-infected pregnant women: Results of a pilot study.

PROBLEM: Recently characterized interferon epsilon (IFNe) protects against sexually transmitted infections, including genital herpes simplex virus (HSV), in animal models. There are no reports of IFNe in genital tract secretions of pregnant women, and data on IFNe in non-pregnant women are limited. This pilot study is the first to measure concentrations of IFNe in vaginal and cervical secretions during pregnancy and compare values between healthy and genital HSV-infected women. METHOD OF STUDY: Vaginal or cervical specimens from 30 pregnant women were obtained from the Global Alliance to Prevent Prematurity and Stillbirth (GAPPS) repository. Cervical samples were collected during the first trimester and vaginal samples across pregnancy. Enzyme-linked immunosorbent assay determined concentrations of IFNe (pg/mL). Data for IFNe were log-transformed and compared by maternal demographics, clinical variables, and HSV status using t tests and linear regression. Repeated measures analysis explored trends across pregnancy. RESULTS: Among the entire cohort, first trimester concentrations of IFNe in vaginal or cervical secretions decreased as body mass index increased (ß = -0.14, P = .0466). Concentrations of vaginal IFNe increased across pregnancy in HSV-infected and healthy women (P = .009). Average vaginal IFNe across pregnancy was lower in women with HSV compared to healthy women (P = .0009). CONCLUSION: Interferon epsilon increased across pregnancy, but was less abundant in women with HSV. This pilot investigation cannot make any definitive conclusions. However, animal models suggest that IFNe may protect against STIs. Thus, larger studies are required to validate expression of IFNe in the reproductive tract of pregnant women with and without genital infections.

Development of the suppository form of human immunoglobulin preparation with high titers of antibodies to herpes simplex virus types 1 and 2 for the treatment of chronic forms of herpetic disease.

In spite of the vast arsenal of therapeutic agents, therapy of herpes virus infection (HVI) is very difficult, particularly in pregnant women, newborns and children in the first years of life, as well as in patients with immune deficiency. In this regard, possibility of using immunoglobulins for the treatment of HVI is currently attracting the attention of doctors. The aim of this work was to develop a suppository form of the drug containing donor immunoglobulins with high levels of neutralizing antibodies to herpes simplex virus types 1 and 2 for the treatment of chronic forms of herpetic disease. The study included the following steps: 1) selection of gamma-globulins with high antibody titer for HSV-1 and HSV-2 ELISA test; 2) determination of the level of neutralizing antibodies in the selected series of gamma-globulins in tests in tissue cultures and animals; 3) lyophilization of immunoglobulins; 4) development of the suppository form of the preparation containing gamma-globulin donors with high levels of neutralizing antibodies to HSV-1 and HSV-2; 5) study of the safety of the activity of neutralizing antibodies to HSV-1 and HSV-2 in the suppository form of the drug with hyaluronic acid used as immunomodulator. As the result of this work, immunoglobulin preparation in the suppository form was developed. The developed preparation meets the requirements for safety and efficacy. It is not toxic or pyrogenic. The problems of clinical use of this drug as a method of HVI therapy are discussed.

Herpes simplex virus and varicella zoster virus: recent advances in therapy.

PURPOSE OF REVIEW: The mainstay of antiviral therapy for the alpha-herpesviruses [herpes simplex virus (HSV)-1, HSV-2, and varicella zoster virus (VZV)] over the past 40 years has been the nucleoside analogues such as aciclovir. Although conventional antiviral therapy has reduced mortality in severe disease, novel agents are needed to address the emergence of resistance and toxicity associated with current second-line therapy. Treatment and prophylaxis of VZV and HSV reactivations remains a challenge. RECENT FINDINGS: A number of compounds have recently been evaluated in human clinical trials, amongst them brincidofovir, an intracellularly acting derivative of cidofovir currently undergoing phase III trials. The helicase-primase inhibitors are a new class of antiviral agent and may circumvent resistance to existing agents. Amenamevir and pritelivir are two examples of these agents that have been evaluated clinically along with novel nucleoside analogues such as valomaciclovir and FV-100. Tenofovir, an agent used in HIV and hepatitis B therapy, may also have a role in the prevention of HSV-2 acquisition and reduce viral shedding. SUMMARY: Although several novel antiviral agents have undergone clinical trials in recent years, all are yet to gain licensure. Brincidofovir appears to be the candidate with most promise for adoption into routine practice in the near future.

Swine Dialyzable Spleen Extract as Antiviral Prophylaxis.

Worldwide, the most highly consumed meat is of porcine origin. The production and distribution of swine meat are affected by diverse health matters, such as influenza and diarrhea, which cause head losses and require the use of antibiotics and other drugs in hog farms. To stimulate newborn piglet immune responses and increase resistance to infections, we developed a spray-drying technique to produce dried swine dialyzable spleen extract (sDSE), an immunomodulator. Based on the size-exclusion ultra performance liquid chromatography quantitative analysis, it was possible to recover up to 58% of the product after the drying process. The biological activity of orally administered dried sDSE increased mouse survival and induced cytokine production in a herpes infection model.

[POSITIVE EFFECTS OF MODERN IMMUNOCORRECTION ACCORDING TO THE ANALYSIS OF CYTOKINES AND SLPI IN PATIENTS WITH PYELONEPHRITIS].

The peculiarities of cytokines as compounds of immunogenesis are shown in the patients having acute (A) and chronic (Ch) pyelonephritis (PN). The combination of antibacterial therapy with Nukleinat and Galavit promotes the positive changes of cytokin-producing ability of immunocompetent cells and decrease in the level of proinflammation cytokines in blood and urine, secretory leucocyte protease inhibitor (SLPI) in urine. In children with PN and adult patients with diagnostically elevated titres of antibodies (IgG) to Herpes simplex virus, Cytomegalovirus are shown the positive effects of Kanephron® H and Proteflazidum, accordingly. Clinico-immunological effects of immunomodulators testify to the expediency of this usage in complex therapy with the aim to modulate the cytokine link of immunity for improvement of the effective treatment in APN and the protection against aggravation of kidney functioning in ChPN.

Anti-herpes virus activities of Achyranthes aspera: an indian ethnomedicine, and its triterpene acid.

The aim of this study was to evaluate the antiviral potential of methanolic extract (ME) of Achyranthes aspera, an Indian folk medicine and one of its pure compound oleanolic acid (OA) against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). The ME possessed weak anti-herpes virus activity (EC50 64.4µg/ml for HSV-1 and 72.8µg/ml for HSV-2). While OA exhibited potent antiherpesvirus activity against both HSV-1 (EC50 6.8µg/ml) and HSV-2 (EC50 7.8µg/ml). The time response study revealed that the antiviral activity of ME and OA is highest at 2-6h post infection. The infected and drug-treated peritoneal macrophage at specific time showed increased level of pro-inflammatory cytokines (IL6 and IL12). Further, the PCR of DNA from infected cultures treated with ME and OA, at various time intervals, failed to show amplification at 48-72h, similar to that of HSV infected cells treated with acyclovir, indicating that the ME and OA probably inhibit the early stage of multiplication (post infection of 2-6h). Thus, our study demonstrated that ME and OA have good anti-HSV activity, with SI values of 12, suggesting the potential use of this plant.

Moxibustion activates host defense against herpes simplex virus type I through augmentation of cytokine production.

Moxibustion is a technique used in traditional oriental medicine, the aim of which is to cure and/or prevent illness by activating a person's ability for self-healing. In this study, we assessed how moxibustion would affect the immune system and whether it would augment protective immunity. Mice were treated with moxibustion at Zusanli (ST36) acupoints; we analyzed mortality and cytokine activity in sera after infection with herpes simplex virus type 1 (HSV-1), and cytokine gene expression in the skin and the spleen without a virus challenge. Our study demonstrates that pretreatment of BALB/c mice with moxibustion resulted in a marked increase in the survival rate after infection with lethal doses of HSV-1, and elevated serum levels of IL-1ß and IFN-γ on days 1 and 6 post-infection with HSV-1. Semi-quantitative RT-PCR assay showed that moxibustion treatment augmented the expression of IL-1α, IL-1ß, IL-6, universal-IFN-α, MIP-1α, and TNF-α mRNA in the skin, and IL-1α, IL-1ß, IL-12p40, IL-15, u-IFN-α, MIP-1α, and TNF-α mRNA in the spleen. Moreover, moxibustion induces augmentation of natural killer cell activity. Collectively, our study demonstrates that moxibustion activates protective responses against HSV-1 infection through the activation of cytokine production including IFN, and of NK cells.

Echinacea purpurea polysaccharide reduces the latency rate in herpes simplex virus type-1 infections.

OBJECTIVE: During the latency period of herpes simplex virus type-1 (HSV-1), the virus can occasionally reactivate, travel back to the eye and cause recurrent ocular disease. As this condition arises from the ability of HSV-1 to produce a dormant infection, effective medication to prevent the virus enter a latent state should prevent it. In this study, we applied Echinacea polysaccharide (EP) fraction as prophylactic mediator for latency prevention. METHODS: In order to investigate the protective properties of EP, we evaluated its immunostimulatory functions on different immune aspects that play important roles in latency prevention (particularly IFN-gamma as one of the main indicators of cellular immunity and latency). Finally, we assessed establishment of latency by detection of thymidine kinase gene in trigeminal ganglia of BALB/c mice. RESULTS: We demonstrated that EP promotes immune response, leading to a reduced latency rate, and it has a promising effect on latency prevention. CONCLUSION: EP was able to exert an antiviral action on the development of recurrent HSV-1 disease when supplied prior to infection.

Beta-androstenes and resistance to viral and bacterial infections.

This report illustrates that the beta-androstenes are indeed able to upregulate the host immune response to a level that enables the host to resist lethal infection by viruses or bacteria. These agents consist of a subgroup of steroids, which also mediates a rapid recovery of hematopoietic precursor cells after whole-body lethal radiation injury. In vivo, the androstenes increase the levels of the Th1 cytokines such as IL-2, IL-3, and IFN. Similar to hydrocortisone, they suppress inflammation, but without immune suppression, and have a role in the maintenance of the Th1/Th2 balance and immune homeostasis.

Terapia a laser no tratamento de herpes simples em pacientes HIV: relato de caso / Laser therapy for herpes simplex treatment in HIV patients: case report

O herpes simples é uma infecção ulcerativa mucocutânea de característica crônica e que pode ser recorrente e que tem como agente etiológico duas cepas do vírus herpes simples (HSV). Como advento da AIDS, houve aumento de manifestações clínicas atípicas exacerbadas pela imunossupressão, podendo estas alterar o curso de uma afecção oral, requerendo um tratamento mais incisivo, e vertendo maiores complicações que possam comprometer o estado imunológico do paciente. Relato de caso de indivíduo HIV positivo em tratamento sob administração de HAART recebendo aplicações seriadas de laserterapia nas áreas afetadas pelo vírus do herpes simples. Na presença de sintomas, o herpes pode ser uma fonte de dores, desconforto e de ansiedade e um tratamento adequado faz-se necessário. A laserterapia promoveu uma remissão do quadro de dor e aumentou o nível de conforto do paciente. O laser de baixa potência é usado para obter-se efeitos terapêuticos precisos de bioestimulação de células, analgesia e função anti-inflamatória, favorecendo rápida evolução do quadro e evitando interação medicamentosa com a HAART, promovendo bem-estar e melhora na qualidade de vida desses pacientes.

Herpes simplex is a mucocutaneous ulcerative infection which has a chronic characteristic of being recurrent and it has as an etiologic agent two types of the herpes simplex virus (HSV). With the outbreaking of AIDS, there was an increment in the atypical clinical manifestations mainly because of the immunosupression, as they can alter the path of an oral affection, then requiring a more aggressive treatment and creating more complications that may compromise the individual's immunological status. The case presents an HIV positive individual under treatment administering HAART receiving serial laser therapy applications in the areas affected by the herpes simplex virus. In the presence of symptoms herpes simplex may be a source of pain, discomfort and anxiety and a suitable treatment is necessary. The laser therapy promoted the remission of the pain pattern and increased the comfort level for the patient. The low density laser is used to create precise therapeutical effects of cell biostimulation, analgesy and anti-inflammatory function, promoting rapid evolution of the disease avoiding interaction with the HAART and promoting well being and improvement in the life quality of these patients.

Th-cytotoxic T-lymphocyte chimeric epitopes extended by Nepsilon-palmitoyl lysines induce herpes simplex virus type 1-specific effector CD8+ Tc1 responses and protect against ocular infection.

Molecularly defined vaccine formulations capable of inducing antiviral CD8+ T-cell-specific immunity in a manner compatible with human delivery are limited. Few molecules achieve this target without the support of an appropriate immunological adjuvant. In this study, we investigate the potential of totally synthetic palmitoyl-tailed helper-cytotoxic-T-lymphocyte chimeric epitopes (Th-CTL chimeric lipopeptides) to induce herpes simplex virus type 1 (HSV-1)-specific CD8+ T-cell responses. As a model antigen, the HSV-1 glycoprotein B498-505 (gB498-505) CD8+ CTL epitope was synthesized in line with the Pan DR peptide (PADRE), a universal CD4+ Th epitope. The peptide backbone, composed solely of both epitopes, was extended by N-terminal attachment of one (PAM-Th-CTL), two [(PAM)2-Th-CTL], or three [(PAM)3-Th-CTL] palmitoyl lysines and delivered to H2b mice in adjuvant-free saline. Potent HSV-1 gB498-505-specific antiviral CD8+ T-cell effector type 1 responses were induced by each of the palmitoyl-tailed Th-CTL chimeric epitopes, irrespective of the number of lipid moieties. The palmitoyl-tailed Th-CTL chimeric epitopes provoked cell surface expression of major histocompatibility complex and costimulatory molecules and production of interleukin-12 and tumor necrosis factor alpha proinflammatory cytokines by immature dendritic cells. Following ocular HSV-1 challenge, palmitoyl-tailed Th-CTL-immunized mice exhibited a decrease of virus replication in the eye and in the local trigeminal ganglion and reduced herpetic blepharitis and corneal scarring. The rational of the molecularly defined vaccine approach presented in this study may be applied to ocular herpes and other viral infections in humans, providing steps are taken to include appropriate Th and CTL epitopes and lipid groups.

Interleukin-12 redirects murine immune responses to soluble or aluminum phosphate adsorbed HSV-2 glycoprotein D towards Th1 and CD4+ CTL responses.

The type of immune response elicited against HSV-2 infection may be a factor in the frequency and severity of recurrent disease, with non-recurrent status being associated with a Th1-like response. As administration of glycoprotein D subunit formulated with an aluminum-based adjuvant induces predominantly Th2-like immune responses, we sought to assess the ability of IL-12 to redirect anti-HSV immunity towards a Th1 response. Co-administration of gD with IL-12 resulted in gD-specific antibody subclass switching from predominantly IgG1 observed in mice immunized with either gD or gD/AlPO4 to a more balanced combination of IgG1 and IgG2a, and enhanced virus neutralizing activity. Spleen cells from mice immunized with gD and IL-12, and restimulated in vitro with HSV-2, developed into effector cells capable of secreting IFN-gamma and lysing HSV-2 infected targets, while those obtained from gD or gD/ALPO4 immunized mice did not express lytic activity. In vitro studies determined that these CTLs were CD4+ and that the cytotoxicity was primarily perforin dependent. Vaginal challenge with HSV-2 demonstrated that IL-12 co-administration with gD resulted in increased efficacy of this vaccine as compared to administration of gD antigen alone. This acquired protection persisted up to 1 year. Finally, adsorbing gD and IL-12 to AlPO4 decreased the optimal dose of IL-12 required to enhance gD immunogenicity and shift responses towards a Th1-like profile.

Does a viral infection cause complex regional pain syndrome?

In 1990 Omura, Y. reported that Herpes Simplex Virus Type 1 as the major cause of chronic intractable pain and its effective treatment using mixture of EPA & DHA with Selective Drug Uptake Enhancement Method. Subsequently among the other causes of pain, he included Chlamydia Trachomatis, Borrelia Burgdorferi, Mycobacterium Tuberculosis, human Herpes Virus type 6, and Circulatory Disturbances. In order to test possible involvement of viral infection in Complex Regional Pain Syndrome (CRPS), a disease which usually occurs in the extremities, we did a study of 17 patients with CRPS. They were examined for Herpes Simplex Virus (HSV) and Varicella Zoster Virus (VZV) by measuring IgG and IgM antibody titers, and 14 of these patients were also examined for Cytomegalo-Virus (CMV). As a control group 100 healthy Japanese employees at SRL, Inc. were also studied. In CRPS group, HSV IgG was positive in 12 of the 17 patients with an average antibody titer of 90.0 EIA value. VZV IgG was positive in all 17 patients with an average antibody titer of 26.8 EIA value. CMV IgG was positive in all 14 patients with an average antibody titer of 66.6 UA/ml. In control group, HSV IgG was positive in 54 subjects with an average antibody titer of 42.3 EIA value. VZV IgG was positive in 97 subjects with an average antibody titer of 26.2 EIA value. CMV IgG was positive in 82 subjects. There were no significant differences of positive rate of IgG antibody for the three viruses between patient and control groups. Although the difference was not significant, the average antibody titers of HSV in CRPS group were more than twice of those in healthy group. Antibody titers were almost equal in both groups for VZV. Possibly, some people in the control group who had latent virus, were also asymptomatic. In 2000, Takasaki, I. et al. in a separate animal study, inoculated with HSV Type-I the shin of the mouse causing allodynia and hyperalgesia (which are some of the characteristic findings seen in CRPS in humans). Also, VZV, which causes shingles which is sometimes followed by Post-Herpetic Neuralgia (PHN), is in the same family of HSV. As PHN resembles CRPS in symptoms, it is possible that HSV contributes to CRPS. Therefore, virus infection theory is an attractive hypothesis that accounts for many enigmas of CRPS.

Psychoneuroimmunology and psychosomatic medicine: back to the future.

OBJECTIVE: Although psychological modulation of immune function is now a well-established phenomenon, much of the relevant literature has been published within the last decade. This article speculates on future directions for psychoneuroimmunology research, after reviewing the history of the field. METHODS: This review focuses on human psychoneuroimmunology studies published since 1939, particularly those that have appeared in Psychosomatic Medicine. Studies were clustered according to key themes, including stressor duration and characteristics (laboratory stressors, time-limited naturalistic stressors, or chronic stress), as well as the influences of psychopathology, personality, and interpersonal relationships; the responsiveness of the immune system to behavioral interventions is also addressed. Additionally, we describe trends in populations studied and the changing nature of immunological assessments. The final section focuses on health outcomes and future directions for the field. RESULTS: There are now sufficient data to conclude that immune modulation by psychosocial stressors or interventions can lead to actual health changes, with the strongest direct evidence to date in infectious disease and wound healing. Furthermore, recent medical literature has highlighted a spectrum of diseases whose onset and course may be influenced by proinflammatory cytokines, from cardiovascular disease to frailty and functional decline; proinflammatory cytokine production can be directly stimulated by negative emotions and stressful experiences and indirectly stimulated by chronic or recurring infections. Accordingly, distress-related immune dysregulation may be one core mechanism behind a diverse set of health risks associated with negative emotions. CONCLUSIONS: We suggest that psychoneuroimmunology may have broad implications for the basic biological sciences and medicine.

The protective effect of hochu-ekki-to (TJ-41), a Japanese herbal medicine, against HSV-1 infection in mitomycin C-treated mice.

BACKGROUND: Immmunosuppression and infectious disease in cancer patients receiving chemotherapy is a serious problem. Immunopotentiating drugs may show a therapeutic efficacy. MATERIALS AND METHODS: The protective effect of Hochu-ekki-to (TJ-41), a Japanese traditional herbal medicine, on mitomycin C (MMC)-induced immunosuppression has been investigated. Spleen weight, the number of forming colonies of granulocytes and macrophages (CFU-GM) in the bone-marrow cells, natural killer (NK) activity in splenocytes and susceptibility to lethal herpes simplex virus type-1 (HSV-1) infection were evaluated. RESULTS: Oral administration of TJ-41 (2000 mg/kg/day) restored MMC-induced decline of spleen weight. CFU-GM and NK activity (20.6% to 68.4%, 48.8% to 77.7%, 21.1% to 95.1%, respectively). Moreover, MMC treatment resulted in a lethal HSV-1 infection and TJ-41 showed a preventive effect. CONCLUSION: TJ-41 may be beneficial for the treatment of infectious diseases in immunocompromised patients receiving chemotherapeutic drugs.

Role of the hypothalamic pituitary adrenal axis and IL-6 in stress-induced reactivation of latent herpes simplex virus type 1.

Hyperthermic stress induces reactivation of herpes simplex virus type 1 (HSV-1) in latently infected mice and also stimulates corticosterone release from the adrenals via activation of the hypothalamic pituitary adrenal axis. In the present study, we tested the hypothesis that stress-induced elevation of corticosterone potentiates HSV-1 reactivation in latently infected mice. Because of the putative role of IL-6 in facilitating HSV-1 reactivation in mice, the effect of hyperthermic stress and cyanoketone treatment on IL-6 expression in the trigeminal ganglion was also measured. Preadministration of cyanoketone, a glucocorticoid synthesis inhibitor, blocked the stress-induced elevation of corticosterone in a dose-dependent manner. Furthermore, inhibition of corticosterone synthesis was correlated with reduced levels of HSV-1 reactivation in latently infected mice. Hyperthermic stress elicited a transient rise in IL-6 mRNA levels in the trigeminal ganglion, but not other cytokine transcripts investigated. In addition, there was a significant reduction in MAC-3+, CD8+, and DX5+ (NK cell marker) cells in the trigeminal ganglion of latent HSV-1-infected mice 24 h after stress. Cyanoketone blocked the stress-induced rise in IL-6 mRNA and protein expression in the trigeminal ganglion latently infected with HSV-1. Collectively, the results indicate that the activation of the hypothalamic pituitary adrenal axis plays an important role in stimulating IL-6 expression and HSV-1 reactivation in the trigeminal ganglion following hyperthermic stress of mice.

Growth hormone improves the resistance of thermally injured mice infected with herpes simplex virus type 1.

BACKGROUND: Growth hormone (GH) has been shown to promote wound healing and to improve protein metabolism in burned patients. Through immunomodulation, GH has also protected rats infected with Salmonella typhimurium and mice infected with Escherichia coli. In spite of advances in the management of patient care for those with thermal injuries, high mortality rates of burned patients as a result of infections are of special concern. An improvement in the resistance of burned patients to certain infections will make the beneficial role of GH very clear. In this study, therefore, the immunomodulating effects of recombinant human GH (rhGH) in thermally injured mice exposed to opportunistic herpesvirus infections were investigated. METHODS: (1) Burned mice, exposed to herpes simplex virus type 1 (HSV-1), were treated subcutaneously with rhGH (4 mg/kg) and observed for 21 days to determine the protective antiviral effect of rhGH. (2) Because of reports describing a lack of interferon-gamma (IFN-gamma) responsiveness in burned mice, the IFN-gamma-producing ability of the splenic mononuclear cells (SMNC) from burned mice treated with rhGH was examined. (3) Because the generation of burn-associated suppressor macrophages that can inhibit the IFN-gamma production by SMNC has been previously described, the suppressor cell activities of macrophages from burned mice treated with rhGH were examined. RESULTS: After exposure to lethal amounts of HSV-1, mice treated with rhGH displayed a reduced mortality rate compared with control mice treated with saline. SMNC from burned mice treated with rhGH produced IFN-gamma, whereas this cytokine was not produced by SMNC from burned mice treated with saline. Also, an inhibition of the generation of burn-associated suppressor macrophages was displayed in burned mice treated with rhGH. CONCLUSION: Exogenous administration of rhGH caused an improvement in the resistance of burned mice to HSV-1 infection. In burned mice treated with rhGH, the impaired IFN-gamma responsiveness was restored and the generation of burn-associated suppressor macrophages was inhibited. IFN-gamma, a typical antiviral cytokine induced by rhGH through the regulation of the suppressor macrophage generation, may therefore play a role in the protection of burned mice infected with a lethal amount of HSV-1.