Genital herpes: epidemiology and pathophysiology. Update and new perspectives

Genital Herpes simplex virus (HSV) is a sexually transmitted disease (STD) which affects millions of people worldwide and is mainly due to HSV type 2. Seroprevalence rates as high as 60-90% have been reported in developing countries. In developed countries, 20% of the general population is HSV2 seropositive. Recent epidemiological surveys employing type-specific antibody assays show that the prevalence of HSV-2 infections is rising at an alarming rate. Also, the epidemiology is changing with an increasing incidence of first episodes caused by HSV-1. The natural history of HSV infection includes acute or subclinical first episode mucocutaneous infection, establishment of neuronal latency, and intermittent virus reactivation with or without associated symptoms. Although this sequence of events has been recognized for more than five decades, little is known about the exact mechanism of latency and reactivation. Almost all persons with HSV2 infection will have recurrences. Recent data show that many of these infections are subclinical: subclinical shedding can be documented in over 80% of HSV2 seropositive individuals who deny subclinical lesions. This suggests that patients shed virus and transmit it even in the absence of clinical signs and that genital herpes should be redefined as a chronic rather than an intermittent disease.     

Herpes. Transmission and viral shedding

Herpes simplex virus infections are transmitted through contact with infected oral or genital secretions. The virus can be present on mucosa during a symptomatic recurrence or asymptomatically. Most transmissions to neonates and sexual partners occur during asymptomatic viral shedding. The frequency of viral isolation in the absence of lesions ranges from 2% to 6% of days; however, studies using more sensitive tests, such as polymerase chain reaction, show that viral shedding can occur on the average 28% of days.     

Herpes. Atypical clinical manifestations

Herpes simplex viruses (HSV) 1 and 2 are responsible for genital herpes which is usually recognized as vesicles that ulcerate and eventually heal but recur periodically. Atypical genital herpes is often described in immunocompromised patients and can present as large, chronic, hyperkeratotic ulcers. Acyclovir-resistant HSV is occasionally isolated from such ulcers. Most cases of HSV infection reproduce subtle signs and symptoms, or more commonly, asymptomatic viral shedding. Such subclinical presentations may be responsible for most of the 30% increase in the prevalence of genital herpes in the United States during the past two decades.     

Evidence of latency and reactivation of both herpes simplex virus (HSV)-1 and HSV-2 in the genital region

While superinfection with different herpes simplex virus (HSV) types has been demonstrated in animals, the ability of the two HSV types to colonize and reactivate in the same anatomic region in humans has not been well demonstrated. In 6 patients, both HSV-1 and HSV-2 was recovered from genital lesions. In 4 of them, who initially acquired genital HSV-1 infection, subsequent HSV-2 infection presented as a prolonged episode of genital lesions and a marked increase in the frequency of genital recurrences. While most of the subsequent clinical reactivations were HSV-2, in 2 patients the recurrence rate of genital HSV-1 increased after the acquisition of HSV-2. These data demonstrate the ability of a second HSV type to infect the same anatomic region and illustrate the difference in reactivation frequency of the two types in the same person. Typing of HSV isolates may be useful in persons with recent alteration in recurrence rates of genital HSV.     

DNA immunization against experimental genital herpes simplex virus infection

A nucleic acid vaccine, expressing the gene encoding herpes simplex virus (HSV) type 2 glycoprotein D (gD2) under control of the cytomegalovirus immediate-early gene promoter, was used to immunize guinea pigs against genital HSV-2 infection. The vaccine elicited humoral immune responses comparable to those seen after HSV-2 infection. Immunized animals exhibited protection from primary genital HSV-2 disease with little or no development of vesicular skin lesions and significantly reduced HSV-2 replication in the genital tract. After recovery from primary infection, immunized guinea pigs experienced significantly fewer recurrences and had significantly less HSV-2 genomic DNA detected in the sacral dorsal root ganglia compared with control animals. Thus, immunization reduced the burden of latent infection resulting from intravaginal HSV-2 challenge, and a nucleic acid vaccine expressing the HSV-2 gD2 antigen protected guinea pigs against genital herpes, limiting primary infection and reducing the magnitude of latent infection and the frequency of recurrent disease.     

Genital herpes. Type-specific antibodies for diagnosis and management

The high incidence of unrecognized genital herpes infections and the role of such undiagnosed infections in continuing the spread of genital herpes has been due, in part, to the limited availability of accurate serologic assays for herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). Type-specific serology test kits for HSV diagnosis have been developed and are expected to be widely available in 1998. Clinicians should understand the proper application of these new test and in addition, should be aware that older, inaccurate test will remain on the market for the foreseeable future.     

The relationship among genital herpes simplex virus, stress, and social support.

Examined the role of stress in activation of genital herpes simplex virus (HSV) lesions, as mediated by social support, in 59 adults who had self-reported culture-positive genital HSV for at least 10 mo. Retrospective reports of HSV symptoms revealed that duration of disease and herpes-specific social support were significant moderators of the relation between stress and number of HSV recurrences (HSV-R) in the preceding 12 mo. When duration of disease was short (     

Protective vaccination against primary and recurrent disease caused by herpes simplex virus (HSV) type 2 using a genetically disabled HSV-1

The vaccine potential of a mutant herpes simplex virus (HSV) type 1, with a deletion in the glycoprotein H (gH) gene, was evaluated. The virus requires a gH-expressing cell line for multi-cycle growth but can complete a single cycle of infection in noncomplementing cells. Such viruses, termed DISC (disabled infectious single cycle) viruses, should be safe, yet still able to stimulate humoral and cell-mediated responses against a broad range of virus antigens in vaccinated hosts. Prophylactic vaccination of guinea pigs with DISC HSV-1, by ear scarification or direct infection of the vaginal mucosa, afforded a high degree of protection against HSV-2-induced primary genital disease and reduced significantly the frequency of subsequent disease recurrence. There was also a trend toward reduced recurrence following therapeutic vaccination of animals already infected with HSV-2. DISC HSV vaccination, therefore, offers an effective route for control of HSV disease.     

Prevalence of herpes simplex virus type 1- and 2- specific antibodies among the acute, recurrent, and provoked types of female genital herpes

Sixty-eight sera from the acute, recurrent, and provoked types of female genital herpes were compared for the seroprevalence of herpes simplex virus (HSV) types 1 and 2 by immunodot assay using HSV glycoprotein G. In the HSV-1-isolated patients, no HSV-2 antibodies were detected, whereas in the HSV-2-isolated patients, HSV-1 seroprevalence was 9% for the acute type, 89% for the provoked type (P < 0.005), and 55% for the recurrent type (P < 0.05). The natural history of female genital herpes and the possible protective role of pre-existing antibodies in preventing the acquisition or clinical manifestation of a subsequent HSV infection are discussed.     

Distribution of herpes simplex virus type 1 and 2 genomes in the human spinal ganglia

Herpes simplex virus (HSV) is well known for its propensity to cause recurrent oral or genital mucosal infections in humans. HSV-1 is involved primarily in oral lesions, whereas HSV-2 is more frequently involved in genital lesions. Based on this, it is thought that HSV-1 may produce latent infections in trigeminal ganglia, and HSV-2 in the sacral ganglia. However the distribution pattern of latent HSV-1 and HSV-2 infections in spinal ganglia remains unknown. Using the polymerase chain reaction we detected latent herpes HSV-1 and HSV-2 in human spinal ganglia obtained from autopsy material. A pair of primers which were specific for a part of the HSV-1 and HSV-2 DNA polymerase domain were employed. HSV-1 and HSV-2 DNAs were detected in 11 of 40 (28%) and 15 of 40 (38%) cervical ganglia, respectively, 52 of 103 (50%) and 47 of 103 (46%) thoracic ganglia, 16 of 53 (30%) and 17 of 53 (32%) lumbar ganglia, and 3 of 20 (15%) and 3 of 20 (15%) sacral ganglia. These findings suggest that latent HSV-1 and HSV-2 infections have a widespread distribution from the cervical ganglia to sacral ganglia. Importantly this study demonstrated latent HSV-1 infection of both the lumbar and sacral ganglia for the first time.     

The prophylactic effect of immunization with DNA encoding herpes simplex virus glycoproteins on HSV-induced disease in guinea pigs

Plasmid expression vectors encoding herpes simplex virus type 2 (HSV-2) glycoproteins B (gB) or D (gD) were constructed and tested for their ability to immunize guinea pigs against genital HSV infection. Immunization with a plasmid expressing the aminoterminal 707 amino acids (aa) of gB induced humoral immune responses detected by ELISA and virus neutralization. When challenged by vaginal infection, immunized animals were partially protected from genital herpes, exhibiting significantly reduced primary and subsequent recurrent disease. When the gB plasmid was combined with a plasmid expressing full-length gD, immunized guinea pigs developed humoral responses to both proteins and were also significantly protected from viral challenge.     

A retrospective study of 375 patients with genital herpes simplex infections seen between 1973 and 1980

A retrospective survey was performed to study the clinical course of 375 patients with genital herpes simplex infections seen between 1973 and 1980. Genital herpes simplex is increasingly being recognized as a disease of the affluent middle class. Recurrences in this study were most frequently associated with emotional stress (85.9 percent) and by coital friction (66 percent). The enormous psychological burden of this disease resulted in 42 percent of the patients withdrawing from sexual encounters. The study suggests a relatively low index of communicability (25.3 percent) to sexual partners even though neither topical nor systemically administered therapeutic agents seemed to significantly influence the course of disease. When curves were constructed based on patients' statements as to when they experienced a period of protracted remission from disease, 50 percent of those with genital herpes simplex were found to be essentially free of frequently recurring episodes within seven years after the onset of disease.     

Detection of herpes simplex virus type 1 shedding in the oral cavity by polymerase chain reaction and enzyme-linked immunosorbent assay at the prodromal stage of recrudescent herpes labialis

Recrudescent herpes labialis (RHL) is a disease caused by herpes simplex virus (HSV), predominantly type 1 (HSV-1). We have monitored HSV-1 shedding in the oral cavity by polymerase chain reaction (PCR) and enzyme-linked immunosorbent assays (ELISA) using digoxigenin-labeled primers designed to amplify a 278 bp segment of the HSV-1 UL 42 region. Prodromal RHL was confirmed by thermographic imaging in 22 patients. Infectious virus was not detected using tissue culture for virus isolation (0/22). Using PCR and agarose gel electrophoresis, we could detect HSV-1 DNA in 8/22 patients. Using a biotinylated-probe internal to the predicted sequence of the PCR product, HSV-1 DNA was detected in 10/22 patients by ELISA. We conclude that HSV-1 DNA is shed into the oral cavity of patients presenting with sub-clinical RHL and that the PCR-ELISA technique represents a more sensitive method to monitor HSV-1 shedding than conventional tissue culturing or PCR-electrophoresis alone.     

Genital herpes complicating pregnancy

The seroprevalence of herpes simplex virus type 2 (HSV-2) infections among reproductive-aged women in the United States in prevalent. This article discusses HSV and how it effects the pregnant women and neonates. Management of the disease is reviewed, and recommendations for management of HSV during pregnancy are given.     

Contraception and the prevention of sexually transmitted diseases

Sexually transmitted diseases (STDs) are a major cause of ill health in women and their sexual partners and children. Contraceptive methods alter in various ways the risk of acquiring STD but assessment of the odds ratio is difficult due to the many confounding factors. Spermicides have been reported to kill a wide range of bacteria and viruses including HIV in vitro and to protect in vivo from infection by gonorrhoea, chlamydia and pelvic inflammatory disease (organisms unspecified). Spermicides will not cure pre-existing infections. Condoms and diaphragms will give some protection from bacterial and viral infections in all parts of the genital tract. Hormonal contraception and tubal ligation give protection to the upper genital tract but not the cervix. Carcinoma of the cervix follows the same pattern as STDs. The risk of pelvic infection in intrauterine device users is discussed in the chapter by Bromham (pp 100-123, this issue).     

Frequency of symptomatic and asymptomatic herpes simplex virus type 2 reactivations among human immunodeficiency virus-infected men

Herpes simplex virus (HSV) infection is common in persons coinfected with human immunodeficiency virus (HIV). In a prospective study, daily viral cultures of the mouth, genitals, and rectum were collected from 68 HIV-positive and 13 HIV-negative men who have sex with men. Subjects completed a median of 57 days of follow-up. Anogenital HSV-2 cultures were positive on 405 (9.7%) of 4167 days for HIV-positive men and on 24 (3.1%) of 766 days for HIV-negative men. Most reactivations were perirectal and subclinical. Risk factors for increased HSV-2 shedding among HIV-positive men were low CD4 cell count (odds ratio, 2.5; 95% confidence interval, 1.2-5.4) and antibodies to both HSV-1 and HSV-2 versus HSV-2 only (odds ratio, 1.9; 95% confidence interval, 1.0-3.7). Three isolates obtained from 3 separate subjects were resistant to acyclovir. Thus, subclinical HSV-2 reactivation is an important opportunistic infection in persons with HIV infection. Further studies are necessaryto determine the impact of subclinical HSV-2 reactivation on the natural history of HIV infection.     

Oral famciclovir for the suppression of recurrent genital herpes: a randomized controlled trial. Collaborative Famciclovir Genital Herpes Research Group

CONTEXT: Recurrent genital herpes simplex virus (HSV) may be treated episodically, but this may not be sufficient for patients with frequent recurrences. OBJECTIVE: To determine the efficacy and safety of famciclovir in the suppression of recurrent genital HSV infection. DESIGN: A randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Thirty university, hospital, or private outpatient referral centers in Canada and Europe. PATIENTS: A total of 455 patients (223 men, 232 women) aged 18 years or older with a history of 6 or more episodes of genital herpes during 12 of the most recent 24 months, in the absence of suppressive therapy, received study medication. INTERVENTION: Oral famciclovir, 125 mg or 250 mg 3 times daily or 250 mg twice daily, or placebo for 52 weeks. MAIN OUTCOME MEASURES: Time to the first recurrence of genital HSV infection; the proportion of patients remaining free of HSV recurrence at 6 months; frequency of adverse events. RESULTS: In an intent-to-treat analysis, famciclovir significantly delayed the time to the first recurrence of genital herpes at all dose regimens (hazard ratios, 2.9-3.3; P<.001); median time to recurrence for famciclovir recipients was 222 to 336 days compared with 47 days for placebo recipients. The proportion of patients remaining free of HSV recurrence was approximately 3 times higher in famciclovir recipients (79%-86%) than in placebo recipients (27%) at 6 months (relative risks, 2.9-3.1; P<.001); efficacy was maintained at 12 months. Famciclovir was well tolerated with an adverse experience profile comparable to placebo. CONCLUSIONS: Oral famciclovir (125 mg or 250 mg 3 times daily or 250 mg twice daily) is an effective, well-tolerated treatment for the suppression of genital HSV infection in patients with frequent recurrences.     

Metals pollution in marine sediments of the United Arab Emirates creeks along the Arabian Gulf shoreline

In order to evaluate the association between seropositivity for herpes simplex virus (type 1 and type 2) and cervical intraepithelial neoplacia (CIN), we analysed data from a population-based case-control study of CIN grade II-III which included Norwegian women aged 20 to 44 years, 94 cases and 228 controls. Our objectives were to determine if HSV-1 and/or HSV-2 seropositivity were independent risk factors for CIN, taking human papillomavirus exposure into account, and to elucidate the combined effect of HPV positivity and seropositivity for HSV In logistic regression analyses, the association between HSV-2 or HSV-1 seropositivity and CIN II-III was not explained by HPV (adjusted OR 3.0; 95%, CI 1.3-7.2 and adjusted OR 3.3; 95% CI 1.3-8.4, respectively). In analyses restricted to HPV-16 DNA-positive individuals, seropositivity for HSV-2 increased the risk of CIN (OR 11.1; 95% CI 1.2-105.7), whereas HSV-1 seropositivity was not significantly associated with CIN. In women positive for other HPV types, only HSV-1 seropositivity was associated with CIN (OR 8.5; 95% CI 1.3-55.8). In analyses of the HPV-16-seropositive individuals, neither HSV-1 nor HSV-2 seropositivity was associated with CIN. Compared to the reference group of jointly unexposed subjects, the HPV-16 DNA-positive women who were anti-HSV-2 negative had an increased risk of CIN (OR 29; 95% CI 12-67), whereas the risk in women who were both HPV-16 DNA-positive and HSV-2 was OR=247 (95% CI 31-1996). The estimate of interaction was strong, but did not reach significance, and our findings may suggest that the combined effect of the two viruses is of aetiological importance in cervical carcinogenesis. Furthermore, the results indicate that HPV DNA positivity is not sufficient to explain the sexual behaviour-associated risk of cervical neoplasia and that further studies on the role of genital HSV (type 1 as well as type 2) and other STDs are warranted.     

The effect of gramicidin, a topical contraceptive and antimicrobial agent with anti-HIV activity, against herpes simplex viruses type 1 and 2 in vitro

The effect of an anti-HIV compound, gramicidin, previously used as a topical antibiotic and vaginal contraceptive, on the replication of herpes simplex viruses (HSV) type 1 and 2 has been examined. Human WI-38 fibroblasts were inoculated with either HSV type in the presence of serial dilutions of gramicidin and reduction in viral yield was measured by ELISA. The 50% inhibitory dose (IC50) of gramicidin against 3 HSV-1 and 4 HSV-2 isolates was equal to 0.3 microgram/ml and was comparable to the efficacy of the anti-HSV agent acyclovir (ACV). The IC50 of gramicidin required to protect WI-38 from cytolytic effect of HSV was 10 micrograms/ml at day 5 postinfection, indicating that at this time point the activity of gramicidin was inferior than that of ACV. Nevertheless, gramicidin suppressed the replication of ACV-resistant thymidine kinase and DNA polymerase HSV mutants at doses effective against ACV-sensitive strains. The results suggest that the antimicrobial and spermostatic agent, gramicidin, has potential against sexually transmitted diseases (STDs) and for prophylaxis of sex-borne HIV and HSV infections.