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.     

Genital herpes infection: a review

Genital herpes infection is life-long and may result in painful and recurrent genital lesions, systemic complications, serious psychosocial morbidity, and rare but serious outcomes in neonates born to infected women, including permanent neurological handicap and death. Herpes simplex virus (HSV)-2 is the principal cause, with an increasing proportion of first-episode disease caused by HSV-1. Genital HSV transmission is usually due to asymptomatic viral shedding by people who are unaware that they are infected and clinical screening fails to detect most infections. Type-specific serological assays can distinguish the two viral subtypes, but these are expensive and currently restricted to a few research settings. Most infections are asymptomatic, or cause a mild illness which does not lead to health service attendance; but the limited evidence suggests a rise in disease incidence, perhaps related to a fall in HSV-1 age-specific prevalences. The prevalences of HSV genital infections increase with age and numbers of sexual partners, with higher rates in specific ethnic and low socioeconomic groups. However, infection is not restricted to high-risk populations. Antiviral agents, such as acyclovir, can reduce disease severity, prevent recurrences and shorten periods of viral shedding, but currently there are no effective population control measures. This may change with the advent of HSV vaccines, if their safety and long-term efficacy are confirmed. Possible applications for vaccines may include the suppression of disease and recurrences in patients with genital infections (immunotherapy), the prevention of viral transmission to their seronegative partners, and immunoprevention through vaccinating the latter. Economic evaluations of existing and potential control strategies, age-specific population HSV-1 and 2 seroprevalence studies for targeting future interventions, and cohort studies to elucidate the natural history of HSV-2 infections are needed.     

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.     

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.     

Detection of immunoglobulin M antibodies to glycoprotein G-2 by western blot (immunoblot) for diagnosis of initial herpes simplex virus type 2 genital infections

Western blots (immunoblots) for the detection of immunoglobulin M (IgM) antibodies specific for herpes simplex virus type 1 (HSV-1) and HSV-2 in patients' sera were developed. The locations of the type-specific glycoprotein G (gpG-2) of HSV-2 (92- and 140-kDa forms) and glycoprotein C of HSV-1 (gpC-1), which carries mostly type-specific antigenic epitopes, were checked with specific monoclonal antibodies. Western blot assays for IgM antibody to gpC-1 or gpG-2 were performed after depletion of IgG by precipitation with anti-human IgG. In patients with primary HSV-2 genital infections, seroconversion of IgM and IgG antibodies to both the 92- and 140-kDa forms of gpG-2 was observed, although both antibodies appeared in convalescent-phase serum after the first week. IgM and IgG antibodies to low-molecular-size polypeptides (40 to 65 kDa) were the first antibodies observed in patients with primary infection, but these antibodies were cross-reactive with HSV-1 and HSV-2. However, in patients with recurrent HSV-2 infections, IgG antibodies to both forms of gpG-2 and the low-molecular-size polypeptides were found no matter how early after onset the patient was bled, and IgM to gpG-2 did not appear. In patients with nonprimary initial genital HSV-2 infections, IgG antibody to HSV-1 was demonstrated in the first serum specimen, and HSV-2-specific IgM was found in 39% of the serum specimens. Hence, the Western blot assay can be used to test for IgM antibody to gpG-2, allowing for the retrospective diagnosis of inital HSV-2 infections and its use as a supplementary test to the gpG-2 IgG enzyme-linked immunosorbent assays developed elsewhere. In contrast, IgM antibody to gpG-2 is not usually detected in patients with recurrent HSV-2 infections.     

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.     

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.     

Association between human immunodeficiency virus and herpes simplex virus type 2 seropositivity among male factory workers in Zimbabwe

To determine the seroprevalence of herpes simplex virus type 2 (HSV-2), to identify correlates of infection, and to describe the correlation with human immunodeficiency virus (HIV) seropositivity, 224 HIV-negative and 191 HIV-positive male factory workers in Zimbabwe were screened for HSV-2-specific antibodies. HSV-2 seroprevalence was 35.7% among HIV-negative subjects and 82.7% among HIV-positive subjects. The weighted estimate of HSV-2 seroprevalence in this population is 44.6%. The correlation between HIV and HSV-2 remained significant after controlling for multiple sex partners, paying for sex, and history of sexually transmitted disease (adjusted odds ratio, 8.0; 95% confidence interval, 4.8-13.1). If the association between HSV-2 and HIV is causal, then the high seroprevalence of HIV and HSV-2 suggests that suppressive HSV-2 treatment should be considered as a strategy to reduce HIV transmission in this population. HSV-2 seroconversion may be a suitable surrogate end point to evaluate HIV prevention interventions.     

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.     

Herpes simplex virus type 2 infections presenting as brainstem encephalitis and recurrent myelitis

We describe here 3 patients with central nervous system infection caused by herpes simplex virus type 2 (HSV-2); one patient with brainstem encephalitis and two with recurrent transverse thoracic myelitis. All three patients showed increased IgG antibodies to HSV in the cerebrospinal fluid (CSF). HSV-2 DNA was demonstrated in the CSF by polymerase chain reaction (PCR) amplification. Upon treatment with acyclovir, one patient with myelitis partially recovered and the others completely recovered. It is important to recognize the wide spectrum of clinical manifestations of HSV-2 infection in the central nervous system (CNS).     

Comparative sequence of human and mouse BAC clones from the mnd2 region of chromosome 2p13

The antiviral effect of acyclovir elaidate in the female guinea pig model of genital herpes was investigated in a series of experiments. The antiherpesvirus effects of this novel compound, 9-(2'-[trans-9"-octadecenoyloxyl]ethoxymethyl)guanine (code no. P-4010), were studied in both primary and recurrent genital herpes in the female guinea pig, following oral gavage or intraperitoneal injection, with different formulations of the compound, and in comparison with acyclovir (ACV) or penciclovir (PCV). The results indicate that compound P-4010 has a greater capability than either ACV or PCV in reducing the clinical symptoms of primary genital herpes induced following the inoculation of herpes simplex virus type 2 (HSV-2) intravaginally into guinea pigs. In addition, the administration of P-4010 twice daily over a 10-day period by the intraperitoneal route (15 to 40 mg/kg of body weight/day) or by oral gavage (50 to 200 mg/kg/day), commencing 4 h subsequent to intravaginal HSV-2 infection, resulted in a degree of reduction in the incidence and severity of spontaneous, recurrent genital herpes in these animals. The findings are discussed in the light of the value and relevance of the female guinea pig model of genital herpes for the assessment of anti-herpes simplex virus compounds.     

Differential mechanism of cytostatic effect of (E)-5-(2-bromovinyl)-2'-deoxyuridine, 9-(1,3-dihydroxy-2-propoxymethyl)guanine, and other antiherpetic drugs on tumor cells transfected by the thymidine kinase gene of herpes simplex virus type 1 or type 2

After they have been transfected with the herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) thymidine kinase (TK) gene murine mammary carcinoma (FM3A) cells become highly sensitive to the growth inhibitory properties of the antiherpetic agents (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), 9(-)[(2-hydroxyethoxy)methyl]guanine (acyclovir, ACV), 9(-)[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG, ganciclovir), and 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-methyluracil (FMAU). BVDU was 100-fold more potent an inhibitor of HSV TK gene-transfected tumor cell growth (50% inhibitory concentration (IC50), 0.0020-0.0047 microM) than FMAU or DHPG (IC50, 0.051-0.277 microM) and 1000-fold more potent than ACV (IC50, 0.42-4.9 microM). As a rule, the test compounds were more cytostatic to HSV-2 TK than HSV-1 TK gene-transfected FM3A cells. This may be ascribed to the higher phosphorylating capacity (Vmax/Km) of HSV-2 TK than HSV-1 TK and/or to the higher TK enzyme levels of the HSV-2 TK gene-transfected FM3A cells than the HSV-1 TK gene-transfected FM3A cells. Thymidylate synthase of the HSV TK gene-transfected FM3A cells appears to be the target enzyme for the cytostatic action of BVDU, but not FMAU, DHPG, or ACV. Instead, the cytostatic activity of DHPG seems to be correlated with its conversion to the triphosphate form and subsequent incorporation into the DNA of HSV TK gene-transfected FM3A cells.     

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.     

Epidemiology of herpes simplex virus type 2 infections in a high-risk adolescent population

The seroprevalence of infection with type 2 herpes simplex virus (HSV-2) was determined in 135 adolescents detained in a juvenile detention facility. A total of 16% of enrollees were seropositive for HSV-2. Age of onset of sexual intercourse, number of lifetime partners, frequency of condom use, and history of sexually transmitted diseases did not predict HSV-2 seropositivity.     

Exchangeability of Qsr1p, a large ribosomal subunit protein required for subunit joining, suggests a novel translational regulatory mechanism

The incidence of herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) in herpes simplex encephalitis (HSE) was investigated using cerebrospinal fluid (CSF) samples from sixty-four cases of HSE. A polymerase chain reaction (PCR) employing primers flanking a region of the HSV thymidine kinase gene common to both HSV-1 and HSV-2 was used to detect HSV in the CSF. HSV-1 and HSV-2 were differentiated by digestion with restriction enzymes. Two enzymes were employed; Aval which cleaved only the HSV-2 gene product and Avall which cleaved only the HSV-1 gene product. Sixty-three cases of HSE were found to be due to HSV-1; one case due to HSV-2. These data confirm previous observations that HSV-2 is a rare cause of post-neonatal herpes encephalitis but indicates that a PCR procedure capable of detection of both viruses is essential for efficient diagnosis of HSE.     

Effects of the estrous cycle on local humoral immune responses and protection of intranasally immunized female mice against herpes simplex virus type 2 infection in the genital tract

This study demonstrates that the levels of gB-specific IgG and IgA in vaginal washes of mice immunized intranasally (i.n.) with a recombinant adenovirus vector expressing herpes simplex virus (HSV) glycoprotein B (AdgB8) vary inversely with each other and are dependent on the stage of the estrous cycle. Anti-gB IgA titers in vaginal washes were significantly higher during estrus than diestrus or proestrus, whereas specific IgG titers were significantly higher during diestrus than estrus. This was further demonstrated in hormone-treated mice, where progesterone administration induced a diestrus-like state that resulted in elevated specific IgG-to-IgA ratios. Interestingly, unimmunized mice were only susceptible to intravaginal (ivag) infection with HSV-2 during diestrus. Mice immunized i.n. with AdgB8 and given progesterone were protected from a lethal intravaginal HSV-2 challenge, despite the fact that virus replication was present for 4 days postchallenge. Further, high numbers of gB-specific IgA and IgG antibody-secreting cells were present in both the genital tracts and the draining iliac lymph nodes of i.n.-immunized, but not unimmunized, mice 6 days following ivag HSV-2 challenge. These results demonstrate that the levels of specific antibodies in the female genital tract are dependent on the stage of the estrous cycle. Furthermore, i.n. AdgB8 immunization provided a significant level of protection and specific IgA and IgG antibody-secreting cells in the genital tissues during resolution of an ivag infection with HSV-2.     

Recurrent ascending myelitis: an unusual presentation of herpes simplex virus type 1 infection

We report on a healthy female with a unique relapsing transverse myelitis accompanied by herpes simplex virus type 1 (HSV-1) infection. Magnetic resonance imaging showed cord enlargement and increased signal intensity on T1-weighted image with gadolinium enhancement from T-4 to T-10 during the first attack and from C-1 to C-2 during the second episode. She was not diagnosed during the first attack. During the second episode, laboratory studies disclosed IgM and IgG antibodies to HSV at the outset with greater than fourfold increases in antibody levels in the serum and cerebrospinal fluid (CSF). Cells cultured from the CSF were positive for HSV-1 according to the immunofluorescence method. The presence of HVS-1 DNA in CSF was documented by polymerase chain reaction (PCR) technique. Acyclovir was given with a partial recovery. We anticipate that PCR assay of CSF will assist early diagnosis of herpetic central nervous system disorders.     

Reactivated herpes simplex virus infection as a possible cause of dry socket after tooth extraction

This study was designed to evaluate a possible association between reactivated herpes simplex virus type 1 (HSV-1) infection after lower third molar extraction and development of dry socket (DS). The HSV-1 antibody response was analyzed before and after tooth removal by enzyme-linked immunosorbent assay and immunoblotting in 208 patients. History of previous possible oral herpes reactivation was evaluated by a questionnaire that was based on self-rated frequency of oral cold sores. Tobacco users were identified. The anatomic proximity of the root apex to the mandibular nerve canal was classified radiographically before extraction. Fifteen patients (7%) developed DS after tooth extraction. Eleven of the 15 DS patients (73%) were HSV seropositive as compared with 7 of 15 (47%) in the matched control group. Seven of the 11 seropositive DS patients have shown HSV-1 reactivation by an increase of specific polypeptides, predominantly gB, gC, gD and ICP 4 and 6, in the immunoblot test. No change in HSV-1 reactivity was observed in control sera. DS patients reported a high frequency of oral cold sores (64%) compared with the controls (33%). Tobacco use was not found to influence the frequency of cold sores or the development of DS. A close radiographic proximity between the mandibular canal and root apex was more common (P < .05) in DS patients. The results indicate that extraction of a mandibular third molar could be a possible cause of reactivation and recurrence of an HSV-1 infection.(ABSTRACT TRUNCATED AT 250 WORDS)