Herpes immunization—on the threshold

Objectives To review the history, public health importance and current status of vaccines intended for the prevention and treatment of genital herpes simplex virus infection.
Background Primary and recurrent genital herpes remains a significant public health problem. Prophylactic and therapeutic vaccines offer an important strategy for control of genital herpes.
Methods Literature review.
Results For more than half a century the development of a safe and effective herpes simplex virus (HSV) has remained an elusive goal. Factors complicating vaccine development have included the complex natural history of HSV infection, an intricate viral genome which has made production of simple tissue culture attenuated live viral vaccines impossible, a general lack of understanding regarding what constitutes protective immunity and an excess of poorly conceived and seriously flawed clinical research. Over the past decade prospects for developing an effective vaccine have brightened as advances in basic immunology and molecular biology have increased our understanding of HSV, and as clinical investigators have taken lessons from the mistakes of earlier research. Investigative teams both in academic centers and in industry are now making excellent progress toward the development of HSV vaccines.
Conclusions The combination of increased understanding and focused application is expected to result in the development of safe and effective HSV vaccines which should be available to physicians within this decade. The goal of the prophylactic vaccine will be to prevent symptomatic primary genital infection and reduce the likelihood the patient will establish latent infection and experience recurrent disease. The therapeutic vaccines are designed for patients who experience recurrent infections with the intended benefit of reduced symptomatic and subclincial recurrences.     

Therapy of banal HSV lesions: molecular mechanisms of the antiviral activity of zinc sulfate]

Preparations of heparin in combination with the physiologically harmless and even beneficial zinc sulphate are available for the topical treatment of superficial mucocutaneous lesions caused by HSV (herpes simplex virus). We study the molecular mechanism of the antiviral effects of zinc ions. A concentration of 100 mumol/l Zn2+ in the culture medium reduces the virus yield in a HSV infected AGMK cell line to less than 1/1000 of the control. At this concentration zinc sulphate does not exert any major cytotoxic effects, nor does it block the synthesis of viral or cellular DNA. Free virus, however, is inactivated by 8 orders of magnitude by 15 mmol/l zinc sulphate within a few hours. The inactivated virus is limited in the glycoprotein-dependent functions adsorption and penetration. Electron micrographs show massive deposition of zinc onto virion components. The dramatic antiviral effect in vivo is therefore explained by an inhibition of virion glycoprotein functions after accumulation of zinc in the virion, presumably by binding to sulphhydryl groups of glycoprotein B.     

间接免疫荧光法检测生殖器疱疹病毒

目的:评价间接免疫荧光试验(IFA)在生殖器疱疹(GH)诊断中的应用价值。方法:采用以单纯疱疹病毒(HSV)型共同性单克隆抗体为夹心的IFA法,检测了120例临床诊断为GH患者皮疹中的HSV,并与病毒培养法进行比较。结果:IFA检测HSV的总阳性率为85.8%,高于病毒培养法的阳性率(70.8%,χ2=12.04,P<0.01)。两种方法检测GH水疱内的HSV阳性率分别为93.3%和90.0%,无明显差异(χ2=1.96,P>0.05);而检测糜烂和结痂性皮疹内的HSV时,IFA的阳性率分别为92.6%和69.4%,均分别高于病毒培养法(75.9%,χ2=5.82,P<0.05;47.2%,χ2=14.17,P<0.01)。结论:IFA法具有简单、快速、敏感性高的优点,适于检测GH患者皮疹内HSV,有临床实用价值。     

Medical application of herpes simplex virus

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are important human pathogens that cause a variety of diseases from mild skin diseases such as herpes labialis and herpes genitalis to life-threatening diseases such as herpes encephalitis and neonatal herpes. A number of studies have elucidated the roles of this virus in viral replication and pathogenicity, the regulation of gene expression, interaction with the host cell and immune evasion from the host system. This research has allowed the development of potential therapeutic agents and vectors for human diseases. This review focuses on the basic functions and roles of HSV gene products and reviews the current knowledge of medical applications of genetically engineered HSV mutants using different strategies. These major HSV-derived vectors include: (i) amplicons for gene delivery vectors; (ii) replication-defective HSV recombinants for vaccine vectors; (iii) replication-attenuated HSV recombinants for oncolytic virotherapy.     

生殖器溃疡中单纯疱疹病毒的检测和分型

目的：了解性病门诊生殖器溃疡患者中单纯疱疹病毒（HSV）感染情况，并评价聚合酶链反应（PCR）－微孔板反向杂交检测和分型方法在生器疱疹诊断中的意义。方法：采用病毒分离培养、普通PCR和PCR－微孔板反向杂交法同时对200份生殖器溃疡标本作了HSV检测与分型。结果：PCR－微孔板反向杂交法的敏感性和特异性分别为98．1％和95．9％，PCR－微孔板杂交法分型结果与病毒分离培养法和普遍PCR的分型结果完全相符。生殖器溃疡中HSV检出率为30％（60／200），其中HSV－2感染占96．7％（58／60）。结论：HSV－2是性病门诊患者生殖器溃疡的主要病因之一，PCR－微孔板反向杂交法是一种适用生殖器溃疡标本中HSV的检测与分型的快速、敏感和特异的诊断方法。     

Polymerase chain reaction for diagnosis of genital herpes in a genitourinary medicine clinic

BACKGROUND: Polymerase chain reaction (PCR) has well established advantages over culture for diagnosis of herpes viruses, but its technical complexity has limited its widespread application. However, recent methodological advances have rendered PCR more applicable to routine practice. Aim: To compare automated PCR with viral culture for diagnosis of genital herpes. METHODS: We studied 236 patients presenting with clinical features suggestive of genital herpes at an inner city genitourinary medicine clinic. Two swabs were taken from each patient. Cell culture and typing were performed by standard methods. Automated PCR was performed using the LightCycler instrument and the infecting viral type was determined by restriction endonuclease digestion of amplicons. RESULTS: 109 patients (46%) had a positive test for herpes simplex virus (HSV). In 88, both PCR and culture were positive; in 21 PCR only was positive. With both detection methods, lesion duration and morphology were associated with HSV detection. Compared with culture alone, use of PCR increased sensitivity by 13.3% in specimens from vesicular lesions, by 27.4% from ulcerative lesions, and by 20.0% from crusting lesions. CONCLUSIONS: We advocate adoption of automated PCR as an efficient HSV detection and typing method for diagnosis of genital herpes in routine clinical practice. PCR allowed rapid laboratory confirmation of the diagnosis and increased the overall HSV detection rate by 24%.     

Update on antiviral therapy for herpes simplex virus infection

ABSTRACT: The prevalence of infection with herpes simplex virus (HSV) continues to increase largely due to the inability of current antiviral agents to eradicate latent infection. This article reviews strategies to slow the transmission of HSV infection, most importantly through the development of vaccines, as well as established and emerging choices for treatment of primary and recurrent genital herpes, herpes labialis, infections in immunocompromised hosts, and acyclovir-resistant infections. The role of chronic suppressive therapy in the management of genital herpes as well as its potential impact on transmission rates will also be discussed.
Herpes simplex virus (HSV) is a widespread pathogen in the United States, with more than 100 million U.S. citizens having serologic evidence of HSV-1 infection and 40–60 million, nearly one-fifth of the adolescent and adult population, infected with HSV-2 (1,2) . The prevalence of HSV-2, the major cause of genital herpes, has increased 30% since the late 1970s (2) . The fact that most of those infected with HSV are asymptomatic and yet may still be subclinically shedding virus further complicates efforts to slow the spread of transmission (3) . Therefore proper management of herpetic infections requires that the clinician be able to effectively diagnose those with HSV infection, to educate them regarding means of spread and symptoms indicative of infection, and to adequately treat infections which are identified in order to alleviate patient symptoms and slow the transmission of the virus. We review options for preventing infection, treating primary infections, and treating recurrent infections in order to accomplish these goals.     

Premarket evaluation of the POCkit HSV-2 type-specific serologic test in culture-documented cases of genital herpes simplex virus type 2 [see comment

BACKGROUND AND OBJECTIVES: The genital herpes epidemic continues, in part, because patients with subclinical or atypical presentations cannot be identified by most herpes simplex virus (HSV) antibody tests. A new product, POCkit HSV-2, has been developed to rapidly and accurately detect antibodies to HSV type 2 (HSV-2) in capillary blood or serum. GOAL: Sera from patients with culture-documented genital or oral herpes were tested to determine the sensitivity and specificity of the POCkit HSV-2 rapid point-of-care antibody test (Diagnology, Belfast, Northern Ireland). STUDY DESIGN: Sera from 50 patients with culture-documented HSV type 1 (9 oral, 41 genital) and from 253 patients with genital HSV-2 were tested by POCkit HSV-2 for HSV-2 antibodies. Each subject had a positive culture for HSV within 6 months of serum collection. Sera were preselected to include only those that were seropositive to the respective virus subtype by University of Washington Western blot. RESULTS: Compared with viral culture and Western blot analysis, sensitivity of the POCkit HSV-2 test for HSV-2 antibody was 96%; specificity was 98%. CONCLUSION: This test provides rapid, accurate identification of HSV-2 antibody in subjects with established HSV infections.     

单纯疱疹病毒的致病特点及人体抗单纯疱疹病毒免疫

单纯疱疹病毒属双链DNA病毒,主要引起皮肤和黏膜损伤,表现为口唇疱疹、疱疹性皮炎、生殖器疱疹等.潜伏感染、周期性复发是单纯疱疹病毒的致病特性.单纯疱疹病毒感染人体后能激发人体固有和获得性免疫应答,包括固有免疫细胞、细胞因子和T淋巴细胞都参与病毒的清除;宿主细胞还可通过启动凋亡机制抑制单纯疱疹病毒的复制及扩散.但是在某些情况下,该病毒能通过潜伏感染和某些机制逃逸免疫细胞的清除,这也是单纯疱疹病毒不能根除的重要原因.为了减少病毒复发频率,已研究出一些可以作为疫苗的单纯疱疹病毒蛋白,但尚未应用于临床.因此,明确单纯疱疹病毒所诱发的机体免疫反应及其免疫逃逸机制对疾病的预防、治疗及新药研发具有重要意义.     

Famciclovir reduces viral mucosal shedding in HSV-seropositive persons

OBJECTIVE: Many cases of herpes simplex virus (HSV) infection occur through asymptomatic shedding from persons without evidence of clinical disease. This study explores whether famciclovir reduces HSV shedding in HSV-2 seropositive persons with or without a history of symptomatic genital herpes. STUDY DESIGN: One hundred twenty-seven HSV-2 seropositive participants were randomly assigned to 42 days of famciclovir, followed by 14 days of washout and 42 days of placebo, or vice versa. All subjects swabbed the genital/perianal area; those with HSV-1 infection also swabbed the oral area daily for HSV DNA PCR. RESULTS: Famciclovir reduced genital and oral HSV shedding from 11.4% of days during the placebo period to 4.7% of days during famciclovir therapy. The reduction was greater in participants with a history of genital herpes (74%) than in those without such a history (30%). In multivariate analyses, famciclovir protected against total (clinical and subclinical) genital shedding among persons with a clinical history of genital herpes (RR, 0.23; 95% CI, 0.15-0.35; P < 0.001). Among HSV-2 seropositive participants without a history of genital herpes, 60% had HSV detected in the genital area at least once during the study. Famciclovir therapy did not result in a statistically significant reduction in total HSV shedding in participants without a history of genital herpes. CONCLUSION: Famciclovir therapy decreases genital HSV shedding in HSV-seropositive persons, especially those with a history of genital herpes. Overall, antiviral drugs may have varying effects on symptomatic and asymptomatic viral shedding, depending on the clinical history of the disease.     

Herpes serology for dermatologists

Serologic tests for antibodies to herpes simplex virus (HSV) have traditionally played a limited role in the treatment of patients with genital herpes. The epidemiological gold standard has been the Western blot analysis, which is only available in a few research centers and is expensive. The gold standard of diagnosis for HSV infection has been viral culture. Diagnosis by viral culture has severely underestimated the number of individuals infected. The majority of patients who are seropositive for herpes simplex virus type 2 (HSV-2) by Western blot analysis are unaware of their symptoms (unrecognized infection) or have subclinical infection. These patients are unlikely to present for culture. Enzyme-linked immunosorbent assay (ELISA) for the serologic diagnosis of herpes has been available for many years but suffers from poor sensitivity and specificity. Reliable, convenient serologic tests for antibodies that distinguish between prior infection with HSV-1 and HSV-2 have recently become commercially available.     

Epidemiology of genital herpes - recent advances

Genital herpes is a common, distressing infection which, due to increasing incidence world-wide, has become a prominent public health issue over recent years, even throughout the decade of human immunodeficiency virus (HIV). Since the late 1970's, the prevalence of herpes simplex virus type 2 (HSV-2) infection has increased by approximately 30 percent in the US. The number of sufferers world-wide is currently estimated at approximately 86 million people. New serological methods based on the detection of type-specific antibodies to herpes simplex virus (HSV) glycoproteins have clarified issues concerning the true incidence of genital herpes, the modifying effect of prior HSV-1 infections, the changing proportions of HSV-1 genital herpes, and the importance of asymptomatic shedding. Patients' ignorance of their diagnosis along with the occurrence of atypical symptomatology and asymptomatic viral shedding of HSV all contribute to the transmission of genital herpes. Genital ulcer disease, of which genital herpes is the most common cause in developed countries, is an important risk factor in the acquisition and transmission of human immunodeficiency virus (HIV) infection and has contributed to the spread of this disorder. Risk factors for genital herpes HSV-2 are strongly related to lifetime number of sexual partners, number of years of sexual activity, male homosexuality, black race, female gender and a history of previous sexually transmitted diseases (STD). Understanding the epidemiology of genital herpes is of great importance in limiting the spread of this STD. In this review, we summarise current knowledge related to the epidemiology of genital herpes.     

Diagnosis of genital herpes by real time PCR in routine clinical practice

BACKGROUND: Virus isolation in cell culture is the recognised diagnostic gold standard for genital herpes. Although increasing evidence indicates that polymerase chain reaction (PCR) provides a more rapid and sensitive diagnostic method, its implementation in routine diagnostic settings has been limited by concerns over contamination and cost. OBJECTIVE: To evaluate the feasibility of replacing virus culture with PCR for the diagnosis of genital herpes in settings serving large populations of genitourinary medicine (GUM) attendees. METHODS: Genital swabs collected from 233 consecutive GUM attendees with suspected genital herpes were tested in parallel by virus culture and automated real time PCR. Three specimen preparation methods were evaluated and the assay reliability was assessed by repeat testing, comparison with a commercially available assay, and herpes simplex virus (HSV) sequence analysis. Probe melting temperatures (Tm) were used to differentiate between HSV types without additional post-PCR steps. RESULTS: HSV was detected in 79/233 (34%) samples by virus culture and 132/233 (57%) samples by PCR. PCR significantly increased HSV detection in both early (< 5 days) and late (> or = 5 days) presentations and in both first and recurrent episodes. HSV detection and typing by PCR was achieved within less than 4 hours leading to a significant reduction in labour compared to virus culture. Most specimens (120/132, 91%) were typed as HSV-2. Results were highly reproducible. CONCLUSIONS: Real time PCR is a highly reproducible, rapid, and labour efficient method for HSV detection in genital swabs. Its implementation is feasible in routine diagnostic settings.     

Using the evidence base on genital herpes: optimising the use of diagnostic tests and information provision

There have been several important advances in the range of available diagnostic tests for genital herpes simplex virus (HSV) infection in recent years; polymerase chain reaction (PCR) is emerging in routine clinical use and the potential role of type specific serological tests is currently under debate. Several large trials of prophylactic vaccines, subsequently proved to be ineffective, have expanded knowledge of the transmission and epidemiology of HSV infection. This article discusses optimal application of recent research evidence to clinical care, structured around the key issues for patients and their partners. These include acquisition and transmission of genital HSV-1 and HSV-2 infection, the natural history of genital herpes, and the role of partner notification.     

Male Genital Herpes Complicated with Urethral Infection

A 26-year-old man had a primary infection or reinfection of genital herpes due to herpes simplex virus (HSV) type 2 complicated with herpetic urethritis. By analysis of the restriction endonuclease digestion pattern of the viral DNA, two isolates, one from the penile lesion and one from the urethra, were identified as the same strain.     

Incidence of herpes genitalis in Northern Ireland in 1973-83 and herpes simplex types 1 and 2 isolated in 1982-4.

During 1973 - 83 there was a pronounced rise in the number of new cases of herpes genitalis in Northern Ireland. This study of 127 patients with herpes genitalis shows that 30% had herpes simplex virus type 1 (HSV 1) and 70% had herpes simplex virus type 2 (HSV 2) infections. Of 41 sexual contacts who attended, only seven had herpes genitalis (caused in each case by HSV 2); another patient had a history of genital lesions, and one other of oral lesions, but HSV was not isolated from either patient. None of the other sexual contacts had a history of oral or genital infection. Of 31 women with herpes genitalis who consented to undergoing cervical cytology, five had atypical changes (all had primary herpes genitalis). Of these, four were infected with HSV 1 and one with HSV 2.     

Asymptomatic shedding and subsequent transmission of genital herpes simplex virus.

We report the transmission of genital herpes simplex virus (HSV) infection from an asymptomatic woman shedding virus from the cervix to two male sexual partners and further transmission from these two men while their infection was in the prodromal phase. The value of the restriction enzyme analysis of viral deoxyribonucleic acid (DNA) is presented. Guidelines regarding the management of patients who are found to be asymptomatic shedders of HSV are discussed.     

Is HSV serology useful for the management of first episode genital herpes?

BACKGROUND: First episode genital herpes simplex virus (HSV) infections can be classified into three groups, primary genital herpes (no previous exposure to HSV), non-primary first episode (IgG antibody to HSV of the non-presenting type), and first episode with pre-existing IgG HSV antibodies. The use of IgM to classify first episode genital herpes has not been evaluated. OBJECTIVE: To evaluate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of HSV-1 and HSV-2 IgM antibodies for the diagnosis of first episode genital herpes, when compared with clinical diagnosis. METHODS: Patients with a first clinical episode of genital herpes were recruited. Sera were tested for IgG antibodies to HSV-2 using an indirect enzyme linked immunosorbent assay (ELISA). Equivocal results were resolved by western blot. HSV-1 IgG and IgM and HSV-2 IgM antibodies were detected using western blot. RESULTS: 157 patients were recruited. 31 were excluded (missing data or no detectable antibodies and negative viral isolation). Therefore, 126 patients were included in the analysis. 23 (18.3%) had primary genital herpes, 34 (27.0%) non-primary first episode, and 69 (54.8%) had pre-existing genital herpes. The specificity and PPV of HSV IgM was 100%; the sensitivity was 79% and the NPV 85%. CONCLUSION: IgM HSV serology may be useful in the management of some patients with first episode genital herpes and provide an indication of the source of infection. Drawbacks include the low sensitivity and NPV, lack of availability, IgM antibodies may occasionally be produced in response to recurrent infection and, finally, IgM antibodies may take up to 10 days to develop and last 7-10 days.     

Detection of varicella zoster virus in genital specimens using a multiplex polymerase chain reaction

OBJECTIVE: To compare the relative proportions of varicella zoster virus (VZV) and herpes simplex viruses in specimens obtained from the genital lesions of adults presenting with presumed genital herpes infection. METHODS: Swabs of genital lesions from 6210 patients attending general practices, infectious diseases clinics within hospitals, or sexual health centres for treatment of their genital lesions were tested using polymerase chain reaction (PCR) technology. The multiplexed PCR was capable of detecting herpes simplex virus types 1 and 2 (HSV-1, HSV-2), VZV, and cytomegalovirus in a single sample. RESULTS: A total of 2225 patients had viruses detected by PCR. HSV-1 was detected in 36%, HSV-2 in 61%, and VZV in 2.9% of PCR positive samples. Of the 65 patients with VZV genital infection, many were thought to have HSV infection before laboratory testing. CONCLUSIONS: The finding of VZV in nearly 3% of virus positive genital specimens demonstrates that this virus needs to be considered as a differential diagnosis for genital herpetic lesions. Advice provided to patients with VZV genital infection regarding the source of infection, likelihood of recurrence, and potential for transmission of the virus will be different from that given to patients with HSV infection.     

The epidemiology of herpes simplex types 1 and 2 infection of the genital tract in Edinburgh 1978-1991.

INTRODUCTION--The changing epidemiology of genital herpes in Edinburgh is described in relation to herpes simplex virus (HSV) Type 1 and herpes simplex virus Type 2 infection over a period of 14 years. METHODS--2018 episodes of genital herpes in 1794 patients over a 14 year period were assessed. Data on age, sex, sexual orientation, geographical origin and herpes antibodies were also analysed. RESULTS--The proportion of cases that were HSV Type 1 increased over the period from approximately 20% to over 40%. Type 1 infection is more common in the young, in women and as a primary infection. CONCLUSIONS--HSV Type 1 is of increasing importance as a cause of genital herpes in our population. This may reflect changes in sexual attitudes and practises over the past decade.