Papers by Spotswood Spruance
Clinical Infectious Diseases an Official Publication of the Infectious Diseases Society of America, Mar 1, 2000
Despite effective antiviral therapy, HSV infections remain a significant worldwide public health ... more Despite effective antiviral therapy, HSV infections remain a significant worldwide public health problem. Vaccines offer the best hope for controlling spread and limiting HSV disease. This article discusses the pathogenesis and immunobiology of mucocutaneous HSV infections, summarizes the spectrum of diseases caused by HSV, and provides a review of the field of HSV vaccine research. This article also discusses what might be realistically expected of a vaccine intended for control of genital herpes and explores the question of whether a vaccine that is effective in controlling genital HSV disease might also be effective in controlling nongenital HSV disease. The efficacy of such vaccines for the full spectrum of HSV disease will eventually determine the timing and targeting of immunization, ranging from selective immunization in preadolescence to universal childhood immunization as part of the routine childhood regimen.
Journal of Neurovirology, Mar 1, 2004
The authors hypothesized that environmental stimuli induce cytokines that act through an intracel... more The authors hypothesized that environmental stimuli induce cytokines that act through an intracellular cascade, which includes signal transducers and activators of transcription (STATs), to change herpes simplex virus (HSV) gene expression, thereby inducing viral reactivation. The HSV type 1 (HSV-1) latencyassociated transcript (LAT) gene regulates viral reactivation within neurons via an unknown mechanism. HSV-1 deletion mutants that are missing key portions of the LAT gene, particularly the 3 region of the LAT promoter, do not reactivate normally in vivo. The authors hypothesized that STAT transcription factors may bind in this region to regulate viral reactivation. Electrophoretic mobility shift assay (EMSA) experiments were performed by incubating mouse trigeminal ganglion (TG) nuclear extracts with each of three overlapping sequences representing the 3 region of the HSV-1 LAT promoter (referred to as oligos L1, L2, and L3). The ganglionic nuclear extracts bound specifically to oligos L1 and L3, but not L2. Oligos L1 and L3 contain predicted STAT binding sequences whereas L2 does not. Specific binding to oligo L3 (including the TATA box sequence) was supershifted by incubating with anti-STAT1 antibodies, but not by incubating with anti-STAT3 or anti-STAT5a antibodies. Specific L3 binding was reduced by competing with excess unlabeled STAT1 consensus sequences. These results indicate that STAT1, probably as part of a complex, is capable of binding to the LAT promoter on or near the TATA box. Further studies are required to determine if STAT1 is required for LAT expression in vivo. This work supports the hypothesis that interferons act through STAT1 to regulate the expression of HSV-1 LAT. Journal of NeuroVirology (2004) 10, 12-20.
Archives of Dermatology, 1998
To compare valacyclovir hydrochloride with acyclovir in the treatment of recurrent genital herpes... more To compare valacyclovir hydrochloride with acyclovir in the treatment of recurrent genital herpes infection. A multicenter, double-blind, placebo-controlled, randomized, parallel-design study. University clinics (dermatology, gynecology, and infectious diseases) and private practices. One thousand two hundred patients with recurrent genital herpes simplex infections. Patients self-initiated oral therapy with 1000 mg of valacyclovir hydrochloride twice daily, 200 mg of acyclovir 5 times daily, or placebo for 5 days. Resolution of all signs and symptoms of recurrent genital herpes infection. Both drugs were significantly more effective than placebo in speeding resolution of herpetic episodes (median duration, 4.8, 4.8, and 5.9 days, respectively); the hazards ratios for valacyclovir and acyclovir vs placebo were 1.66 (95% confidence interval [CI], 1.38-2.01) and 1.71 (95% CI, 1.41-2.06) (both P < .001). Similarly, valacyclovir and acyclovir significantly hastened lesion healing (hazards ratios vs placebo were 1.88 [95% CI, 1.53-2.32] and 1.90 [95% CI, 1.55-2.34], respectively; P < .001). Pain duration was shorter in valacyclovir- and acyclovir-treated patients (median, 2 vs 3 days). Viral shedding stopped 2.55 times faster in patients treated with valacyclovir and 2.24 times faster in patients treated with acyclovir than in patients treated with placebo. Aborted episodes, in which lesions did not progress beyond the macule or papule stage, tended to occur in more patients treated with valacyclovir (25.9%) or acyclovir (24.8%) than in patients treated with placebo (19.8%). Valacyclovir and acyclovir did not differ significantly with regard to their respective effects on any of the above efficacy parameters. The nature, severity, and frequency of adverse events did not differ among the 3 treatment groups. Twice-daily valacyclovir was as effective and well tolerated in the treatment of recurrent genital herpes simplex virus infection as 5-times-daily acyclovir. Therefore, valacyclovir could prove a useful alternative to acyclovir when convenience of dosing or compliance issues are the prime considerations in treatment.
Annals of Internal Medicine, May 1, 1985
ABSTRACT Recurrent herpes simplex virus infection predisposes to the development of erythema mult... more ABSTRACT Recurrent herpes simplex virus infection predisposes to the development of erythema multiforme in some persons (1) and can lead to a pattern of recurrent erythema multiforme and disabling morbidity. Recent reports of the safety and efficacy of oral acyclovir for the prophylaxis of recurrent herpes virus infections (2-4) suggest a similar application for the prevention of herpes virus related erythema multiforme.
Herpes the Journal of the Ihmf, Dec 1, 2002
Recurrent herpes simplex labialis is associated with mild morbidity, but remains a significant pr... more Recurrent herpes simplex labialis is associated with mild morbidity, but remains a significant problem for people with frequent and/or severe recurrences. Both topical and peroral episodic antiviral treatments of recurrences are modestly effective at reducing the duration of signs and symptoms. Recent studies with high-dose, short-course valaciclovir suggest that maximum benefit from antiviral therapy may be achieved with as little as 1 day of treatment. Topical steroids may be useful in combination with an antiviral agent, but more needs to be learnt about the appropriate strength and duration of steroid therapy before a general recommendation can be made. Selected subgroups of patients are candidates for prophylactic treatment with perorally administered nucleoside antiviral agents. Prophylaxis with topical agents is not effective.
Journal of Interferon Cytokine Research, Jul 1, 2001
Herpes : the journal of the IHMF, 2007
Infection with herpes simplex virus (HSV) has increased in prevalence worldwide over the past two... more Infection with herpes simplex virus (HSV) has increased in prevalence worldwide over the past two decades, making it a major public health concern. Approximately 90% of recurrent HSV type 1 (HSV-1) infections manifest as non-genital disease, primarily as orofacial lesions known as herpes labialis. Improvements in our understanding of the natural history of herpes labialis support the rationale for early treatment (during the prodrome or erythema stages) with high doses of antiviral agents in order to maximize drug benefit. When evaluating the efficacy of different antiviral and anti-inflammatory agents in clinical trials, episode duration, lesion healing time, reduction in maximum lesion size and the proportion of aborted lesions should be used as the most reliable measures of therapeutic efficacy. There has also been considerable research into the most beneficial treatment for recurrent episodes of herpes labialis in immunocompetent individuals. Data from clinical studies confirm t...
New England Journal of Medicine, 2002
Background An effective prophylactic vaccine would help control the spread of genital herpes.
New England Journal of Medicine, 1981
... Peter T. Vickerman, Zaid Chalabi, Philippe Mayaud, Michel Alary, Charlotte H. Watts. (2009) D... more ... Peter T. Vickerman, Zaid Chalabi, Philippe Mayaud, Michel Alary, Charlotte H. Watts. (2009) Dynamic Modeling of Herpes Simplex Virus Type-2 (HSV-2) Transmission: Issues in Structural Uncertainty. Bulletin of Mathematical Biology 71:3, 720-749. 2. ELINE L. KORENROMP ...
New England Journal of Medicine, 1977
We performed daily examination of 80 patients with recurrent herpes simplex labialis to define th... more We performed daily examination of 80 patients with recurrent herpes simplex labialis to define the course of the disease and to identify quantitative and objective measurements for use in monitoring the efficacy of antiviral chemotherapy. Pain, lesion size, mean virus titers from lesion swabs (10(5) plaque-forming units [PFU]) and frequency of virus-positive lesions (89 per cent) were maximal during the first 24 hours and decreased thereafter. Lesion punch-biopsy virus titers increased from a mean of less than 10(1) PFU in the prodromal and erythema stages to a mean of 10(4.7) in the vesicle stage. MEasurements potentially useful in monitoring antiviral efficacy include: time to loss of crust, time to complete healing, intensity and duration of lesion pain, area defined by lesion virus titer and duration of lesion virus excretion, and maximum lesion virus titer after the first visit. Early application of topical antiviral therapy should theoretically be able to alter the course of this disease.
Journal of the American Academy of Dermatology, 2006
The brief period of viral replication in recurrent herpes labialis lesions suggests shorter thera... more The brief period of viral replication in recurrent herpes labialis lesions suggests shorter therapeutic regimens are a logical episodic treatment strategy. We sought to assess the efficacy and safety of single-dose and single-day famciclovir treatments. In all, 701 randomly assigned patients self-initiated therapy with famciclovir (1500 mg once [single dose] or 750 mg twice a day for 1 day [single day]) or placebo within 1 hour of onset of the prodromal symptoms of an episode of herpes labialis. Lesion healing was monitored by diaries and frequent clinic visits. Median healing times of primary (first to appear) vesicular lesions in the famciclovir single-dose, famciclovir single-day, and placebo groups were 4.4, 4.0, and 6.2 days, respectively. There was no significant difference between the famciclovir regimens. Adverse events in the famciclovir groups were similar to placebo. The active arms of this trial were not directly compared to other antiviral regimens. Single-dose famciclovir reduced time to healing of herpes labialis lesions by approximately 2 days compared with placebo.
Journal of Neurovirology, 2004
The authors hypothesized that environmental stimuli induce cytokines that act through an intracel... more The authors hypothesized that environmental stimuli induce cytokines that act through an intracellular cascade, which includes signal transducers and activators of transcription (STATs), to change herpes simplex virus (HSV) gene expression, thereby inducing viral reactivation. The HSV type 1 (HSV-1) latencyassociated transcript (LAT) gene regulates viral reactivation within neurons via an unknown mechanism. HSV-1 deletion mutants that are missing key portions of the LAT gene, particularly the 3 region of the LAT promoter, do not reactivate normally in vivo. The authors hypothesized that STAT transcription factors may bind in this region to regulate viral reactivation. Electrophoretic mobility shift assay (EMSA) experiments were performed by incubating mouse trigeminal ganglion (TG) nuclear extracts with each of three overlapping sequences representing the 3 region of the HSV-1 LAT promoter (referred to as oligos L1, L2, and L3). The ganglionic nuclear extracts bound specifically to oligos L1 and L3, but not L2. Oligos L1 and L3 contain predicted STAT binding sequences whereas L2 does not. Specific binding to oligo L3 (including the TATA box sequence) was supershifted by incubating with anti-STAT1 antibodies, but not by incubating with anti-STAT3 or anti-STAT5a antibodies. Specific L3 binding was reduced by competing with excess unlabeled STAT1 consensus sequences. These results indicate that STAT1, probably as part of a complex, is capable of binding to the LAT promoter on or near the TATA box. Further studies are required to determine if STAT1 is required for LAT expression in vivo. This work supports the hypothesis that interferons act through STAT1 to regulate the expression of HSV-1 LAT. Journal of NeuroVirology (2004) 10, 12-20.
Journal of Medical Virology, 1985
Approximately 30% of persons with frequent episodes of herpes labialis are deficient in the produ... more Approximately 30% of persons with frequent episodes of herpes labialis are deficient in the production of HSV-induced immune-specific interferon (IFN) (Green, 1985). Herpes simplex virus (HSV) strains isolated from persons who make immune-specific IFN and from persons who do not make it were examined for their immunostimulatory capabilities. HSV isolated from the primary oral lesions of two patients deficient in immune-specific IFN production, one person with an intact immune-specific IFN response, HSV types 1 and 2 laboratory strains, and Newcastle disease virus (NDV) were added to cultures of peripheral blood mononuclear cells (PBML) from HSV seropositive donors. All HSV-isolates induced comparable titers of immune-specific IFN. These studies suggest that failure of some patients to develop an immune-specific IFN response is determined by the host, not the virus.
Journal of Interventional Cardiology, 2011
Ideally, percutaneous, mechanical closure of defects of the atrial septum should completely resol... more Ideally, percutaneous, mechanical closure of defects of the atrial septum should completely resolve shunt. To achieve this goal, more information is needed about the factors associated with device failure. Consecutive patients with cryptogenic neurological events who had severe baseline Valsalva shunt (Spencer Grade 5-5+) and intracardiac echocardiography (ICE) defined patent foramen ovale (PFO) who underwent percutaneous PFO closure with the GORE(®) HELEX Septal Occluder device were evaluated for residual 3-month shunt by transcranial Doppler (TCD). We closed 315 PFO patients with the HELEX devices: 15, 20, 25, 30 mm devices in 19, 138, 150, and 8 patients, respectively. Severe residual Valsalva shunt (TCD Grade 5-5+) at 3 months occurred in 23 of 315 (7%) of all patients and in 2 of 108 (2%), 5 of 86(6%), and 16 of 121 (13%) patients with none, Grade 4, and Grade 5-5+ baseline rest shunt, respectively (P = 0.002). At 3 months, rest shunting was essentially abolished by closure. The percent of patients with severe residual Valsalva shunt was also related to device size: 15 mm (0%), 20 mm (4%), 25 mm (10%), and 30 mm (25%) (P = 0.008) and to atrial septal aneurysm. All of these variables were independent predictors of failure by multivariate logistic regression. In an ICE-defined PFO population characterized by severe baseline Valsalva shunt and a high incidence of persistent (rest) shunting, the GORE(®) HELEX Septal Occluder device effectively reduces both provoked and persistent shunt. The causes of device failure are multifactorial. Larger devices perform less reliably suggesting the need for size-specific modifications to improve closure of more severe defects. (J Interven Cardiol 2011;24:366-372).
The Journal of Infectious Diseases, 2005
Herpes simplex virus type 2 (HSV-2) resistance to antiviral drugs has been described primarily in... more Herpes simplex virus type 2 (HSV-2) resistance to antiviral drugs has been described primarily in immunocompromised patients. We report an apparently immunocompetent, human immunodeficiency virus-negative male patient who has experienced repeated HSV-2 genital outbreaks despite receiving antiviral prophylaxis with several different drugs. Several of the HSV-2 genital isolates from this patient have been confirmed as resistant to acyclovir and penciclovir. Antiviral resistance occurred in the setting of long-term prednisone treatment and intermittent acyclovir prophylaxis at suboptimal doses and persisted despite the cessation of oral steroid treatment. The patient's genital herpes outbreaks were not controlled by high-dose prophylaxis with acyclovir, valacyclovir, and famciclovir. Cessation of antiviral prophylaxis resulted in reversion of this patient's HSV-2 isolates to acyclovir and penciclovir sensitivity, although resistant virus reappeared when antiviral prophylaxis was resumed. Transmission of a sensitive HSV-2 strain from this patient to a female sex partner was observed. These observations confirm previous reports that resistance to acyclovir may develop during prophylactic therapy in an otherwise well, immunocompetent patient. These findings support the conclusion that both drug-sensitive and drug-resistant HSV-2 strains established latency in this patient and that both strains are capable of frequent reactivation.
Journal of Infectious Diseases, 1981
Antiviral activity characterized as human interferon (HuIFN) was demonstrated in vesicle fluid fr... more Antiviral activity characterized as human interferon (HuIFN) was demonstrated in vesicle fluid from lesions of recurrent herpes labialis in 18 of 19 otherwise healthy patients. High titers (geometric mean, 29,200 units) were present during the early course of lesion development. Antiviral activity in vesicle fluid was neutralized by antibody to leukocyte (types I) HuIFN (HuIFN-alpha) in the eight patients in whom it was tested. These results indicate that HuIFN-alpha is present in the local lesions of recurrent herpes labialis. HuIFN may have a role in the pathogenesis of recurrent herpesvirus infections.
JAMA: The Journal of the American Medical Association, 1980
In a double-blind, placebo-controlled study, 51 patients with recurrent herpes simplex labialis w... more In a double-blind, placebo-controlled study, 51 patients with recurrent herpes simplex labialis were treated with topical ether or placebo within 24 hours of onset of a lesion. There was no noteworthy difference between groups given ether and placebo in progression of lesions, healing time, duration or intensity of pain, and duration or quantity of virus excretion. The ether also failed to reduce appreciably lesion virus titer, even when lesions were cultured immediately after topical application. Despite these results, 75% of the patients receiving ether and 77% of those receiving placebo reported effective reduction of the severity and duration of lesions. The marked placebo effect in the treatment of recurrent herpes infection helps to emphasize the need for objective measurements and placebo-controlled studies.
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Papers by Spotswood Spruance