Herpes virus infections occur frequently following treatment with fludarabine: results of a prospective natural history study.

We performed a prospective infectious natural history study of 21 patients with low-grade lymphoproliferative disorders receiving fludarabine as initial (n = 5) or salvage (n = 16) therapy. 12 (57%) of these patients developed herpes zoster (n = 9), herpes simplex I (n = 1) or herpes simplex II (n = 2) infections at a median of 8 (range 1-17) months following initiation of fludarabine, with 75% of these having completed therapy. All patients with herpes zoster developed severe post-herpetic neuralgia. Factors differentiating patients developing these infections included older age and low serum IgG or IgA. Based upon these prospective data, we conclude that herpes simplex virus infections frequently occur following fludarabine treatment, necessitating aggressive patient education and new prophylactic strategies.

The equine herpes simplex virus 4 thymidine kinase is a better suicide gene than the human herpes simplex virus 1 thymidine kinase.

The herpes simplex virus type 1 thymidine kinase suicide gene (HSV1tk) together with ganciclovir (GCV) have been successfully used for in vivo treatment of various experimental tumors, and many clinical trials using this system have been launched. With the aim to improve this therapeutic system, we compared the potential efficacy of different herpes simplex virus derived thymidine kinases (HSV1, varicella-zoster virus, equine herpes simplex virus type-4 and Epstein-Barr virus) as suicide genes in association with the nucleoside analogs Acyclovir, ganciclovir and bromovinyldeoxyur- idine. Using various murine and human cell lines expressing these viral tk, we show that HSV1- and EHV4tk are the more efficient suicide genes for the different nucleoside analogs tested. Moreover, EHV4tk expressing murine and human cells were three- to 12-fold more sensitive to GCV than HSV1tk expressing cells. This was correlated with the presence of five-fold higher amounts of the toxic triphosphated-GCV in EHV4- versus HSV1tk expressing cells. Altogether, these experiments underline the potential advantages of the EHV4tk as a suicide gene.

Unidirectional complementation between glycoprotein B homologues of pseudorabies virus and bovine herpes simplex virus 1 is determined by the carboxy-terminal part of the molecule.

The most highly conserved glycoproteins in herpes simplex viruses, homologues of glycoprotein B (gB) of herpes simplex virus, have been shown to play essential roles in membrane fusion during penetration and direct cell-to-cell spread of herpes simplex virions. In studies aimed at assessing whether sequence conservation is reflected in the conservation of functional properties, we previously showed that bovine herpes simplex virus 1 (BHV-1) gB was able to functionally complement a gB- PrV mutant. To analyse in detail the function of gB in BHV-1, and to be able to test for reciprocal complementation between pseudorabies virus (PrV) and BHV-1 gB, we isolated a gB- BHV-1 mutant on a cell line stably expressing BHV-1 gB. Functional analysis showed that BHV-1 gB was essential for penetration as well as for direct cell-to-cell spread of BHV-1, indicating similar functions for PrV and BHV-1 gB. However, PrV gB was unable to complement plaque formation, i.e. direct cell-to-cell spread, or penetration of gB-BHV-1 virions despite its incorporation into the virion envelope. Analysis of cell lines expressing chimeric gB molecules composed of PrV and BHV-1 gB showed that plaque formation of both gB- mutants was complemented when the carboxy-terminal half of the chimeric gB was derived from BHV-1 gB and the amino-terminal half from PrV gB. In the opposite case, unidirectional complementation occurred. Although the chimeric molecules were generally less efficient in complementing infectivity of free virions, a similar complementation pattern was observed. In summary, our data show a unidirectional pattern of transcomplementation between the gB glycoproteins of PrV and BHV-1. This indicates that these proteins are functionally related but not identical. The unidirectional transcomplementation pattern was determined by the provenance of the carboxy-terminal half in chimeric gB proteins indicating that regions which are important for gB function but differ between PrV and BHV-1 reside in this part of gB.

Preliminary comparison of three LightCycler PCR assays for the detection of herpes simplex virus in swab specimens.

Three Herpes Simplex Virus LightCycler polymerase chain reaction assays were compared for the detection of herpes simplex virus in 48 swab specimens. The assays comprised of one in-house assay and two commercial kits: the Artus HSV LC RealArt PCR kit and the Roche LightCycler HSV 1/2 Detection kit. On the whole, the three assays had comparable sensitivities. However, differentiation of herpes simplex virus types 1 and 2 by melting curve analysis was problematic in all assays. Overall, the results highlight the limitations of typing herpes simplex virus by melting curve analysis.

Induction of human immunodeficiency virus 1 replication by human herpes simplex virus 8.

BACKGROUND: Human immunodeficiency virus 1 (HIV-1)-infected individuals are commonly infected with herpes simplex viruses, including cytomegalovirus, herpes simplex virus, varicella-zoster virus, and human herpes simplex virus 8 (HHV-8, also known as Kaposi sarcoma-associated herpes simplex virus [KSHV]). Previous studies have demonstrated that coinfection with herpes simplex viruses can modulate HIV-1 replication. This can occur either through direct interaction between the 2 viruses or through secondary effects resulting from the release of cellular factors in response to infection. OBJECTIVE: To investigate HIV-1 replication in the presence and absence of HHV-8. DESIGN AND METHODS: HIV-1 replication was analyzed following culture of HIV-1-infected CD4(+) T cells in the presence of HHV-8 infected B-cell lines or control, uninfected B-cell lines. To confirm and extend the results of these in vitro studies, HIV-1-infected T cells were injected into human skin transplanted onto severe combined immunodeficient mice. The human skin was also injected with purified HHV-8 or phosphate-buffered saline as a control and HIV replication measured in biopsy specimens taken 5 to 8 days later. RESULTS AND CONCLUSIONS: The results demonstrated a significant increase in HIV-1 replication in the presence of HHV-8 in both the in vitro and in vivo model systems. Although the mechanism responsible for HHV-8 induction of HIV-1 replication remains to be identified, the results indicate that these 2 viruses may interact at the molecular level in coinfected patients, resulting in increased HIV-1 viral load.

A retrospective study of the clinical presentation and outcome of herpes zoster in a tertiary dermatology outpatient referral clinic.

BACKGROUND: This is a retrospective study of the epidemiology and morbidity of herpes zoster and the risk factors for herpes zoster morbidity in Singapore. RESULTS: The mean age of 164 patients with herpes zoster seen at our dermatology clinic between January 1994 and December 1995 was 48.8 years, with a sex ratio of 1:1. The common presenting symptoms were pain (90%), feelings of helplessness and depression (20%), and flu-like symptoms (12%). The commonest prodromes were pain (41%), itching (27%), and paresthesia (12%). Prodromal pain was more frequently experienced by patients aged more than 50 years (42%) than by patients aged less than 30 years (25%). The thoracic (45%) and cervical (23%) dermatomes were the most commonly affected in all age groups. There was no statistically significant difference in the frequency of dermatomal distribution among the different age groups and between the sexes. Pain was experienced by almost all (95%) patients during the course of their disease. It tended to be more severe in older patients. Burning (26%), stabbing (15%), and shooting (15%) pain were the most common types experienced. Post-herpetic neuralgia was significantly more common in older patients. The prevalence of post-herpetic neuralgia decreased over time in all age groups. A higher proportion of older patients (more than 50 years of age) (20%) suffered from post-herpetic neuralgia compared with younger patients (less than 30 years of age) (7%) (not significant). Patients in all age groups considered acute pain (46%) and persistent pain (25%) to be their most unbearable symptoms during the course of herpes zoster. The most significant problems caused by herpes zoster pain were insomnia (25%), misery (feeling helpless and depressed) (20%), limitation of movement (9%), and inability to continue work (8%). Insomnia was significantly more commonly experienced by patients more than 50 years of age (36%) than those less than 30 years of age (P = 0.026). Few patients (9%) consulted their general practitioner (GP) during the prodrome or on the day of appearance of skin eruptions. Most patients (45%) consulted their GP within the first 3 days of the onset of skin eruptions; 33% sought treatment more than 3 days after the appearance of zoster symptoms. Only 30% of patients were willing to pay more than S$200 for antiviral therapy. Most (43%) were only prepared to pay for antiviral treatment if it cost less than S$200. The most important features the patients wished to derive from antiviral therapy were a shortening of the duration of skin lesions (55%) and a reduction in the severity of pain (acute and chronic) (30%). CONCLUSIONS: Our study indicated that older patients (aged more than 50 years) were at a higher risk of developing post-herpetic neuralgia. They were also more likely to suffer morbidity, e.g. insomnia. There is a need to educate patients at risk to identify the prodrome and skin eruptions of herpes zoster so that early antiviral therapy can be considered.

Clinical reactivation of genital herpes simplex virus infection decreases in frequency over time.

BACKGROUND: Visits to physicians for genital herpes simplex virus (HSV) infection continue to increase. Most patients with symptomatic infections have recurrences, but no studies of the long-term clinical course of genital herpes simplex are available. OBJECTIVE: To determine whether the frequency of HSV recurrences decreases over time. DESIGN: Observational cohort study. SETTING: University-based research clinic. PATIENTS: 664 persons with genital herpes simplex followed for at least 14 months. MEASUREMENTS: Patients were classified as having initial or recurrent HSV-1 or HSV-2 infection. Patient-reported recurrences and observed recurrences were recorded in a database; more than 12,000 recurrences were analyzed. RESULTS: Median recurrence rates in the first year of follow-up were one and five per year in patients with newly acquired HSV-1 and HSV-2 infection, respectively; second-year rates were significantly lower in both groups. Patients presenting with recurrent HSV-2 infection had higher rates of recurrence in the first and second years and no significant decrease; significant decreases were detected with longer follow-up. One third of all patients experienced a decrease of two or more recurrences per year between years 1 and 2. Patients infected with HSV-2 who were followed for more than 4 years had a median decrease of two recurrences between years 1 and 5. However, 25% of these patients had an increase of at least one recurrence in year 5, illustrating the variability among HSV-infected persons. Decreases over time among patients who never received suppressive therapy were similar to decreases during untreated periods in patients who received suppressive therapy. CONCLUSIONS: Herpes Simplex virus type 2 infection continues to be a chronic remitting illness. Over time, however, clinically significant reductions occur in a majority of patients. Physicians may wish to periodically assess the need for continued treatment with daily suppressive antiviral chemotherapy.

Seroprevalence of herpes simplex virus infections in a family medicine clinic.

OBJECTIVES: To determine the prevalence of herpes simplex virus (HSV) antibody in a general medical practice setting and to assess the frequency of subclinical infection. DESIGN: Prevalence study. SETTING: A family practice clinic at the University of Washington Medical Center, Seattle. PARTICIPANTS: Five hundred randomly selected patients between the ages of 18 and 45 years. MAIN OUTCOME MEASURES: Serum samples were tested by Western blot assay to detect the presence of antibody to HSV type 1 (HSV-1) and HSV-2. Demographic information and clinical history of oral and genital herpes simplex were obtained. RESULTS: One hundred fourteen patients (23%) were seropositive for HSV-2 antibody, 277 patients (56%) were seropositive for HSV-1 antibody, 59 patients (12%) were seropositive for both HSV-2 and HSV-1 antibodies, and 163 patients (33%) were seronegative for both. Women were almost twice as likely as men to be seropositive for HSV-2 antibody (28% vs 15%, P < .001). Blacks had the highest rates of HSV-2 antibody seropositivity (60%) compared with whites (20%) and Asians (6%) (P < .001). Other demographic correlates of seropositivity included being older, having fewer years of education, and having public insurance. The specificity of a clinical history of genital herpes simplex or sores for HSV-2 infection was high (99%), but the sensitivity was low (27%). CONCLUSIONS: Herpes Simplex virus infection is common among patients seeking primary care. Women, blacks, and patients of lower socioeconomic status are most likely to be seropositive for HSV-2 antibody. The high frequency of unrecognized HSV infection has implications for primary care physicians in counseling patients regarding HSV infection and transmission.

Cost-effectiveness of herpes simplex virus type 2 serologic testing and antiviral therapy in pregnancy.

OBJECTIVE: The purpose of this study was to determine whether serologic testing for herpes simplex virus type 2 (HSV-2) in pregnant women and their partners is cost-effective. STUDY DESIGN: A decision analysis model was developed to investigate the cost-effectiveness of providing type-specific serologic testing at week 15 of pregnancy for all women unaware of their HSV-2 status, and offering antiviral suppressive therapy from week 36 until delivery to all seropositive women. This scenario was compared with current care, in which only a minority of women diagnosed with genital herpes simplex (GH) receives antiviral suppressive therapy (AST). In a third scenario, testing is offered to partners of pregnant women who test seronegative, and antiviral suppressive therapy is offered to the partners who test seropositive. RESULTS: Compared with current care, offering testing and antiviral suppressive therapy to 100,000 pregnant women resulted in an incremental cost of $3.1 million, 15.7 fewer cases of neonatal herpes, 186 fewer cesarean deliveries, and an incremental cost per quality-adjusted life- year gained (QALY) of $18,680. Offering testing and suppressive therapy to both the pregnant women and their partners resulted in an increased cost of $8.6 million, 16.8 fewer cases of neonatal herpes, 192 fewer cesarean deliveries, and an incremental cost per QALY of $48,946 compared with no testing. CONCLUSION: Compared with commonly accepted benchmarks for cost-effectiveness (<$50,000/QALY), type-specific HSV-2 serologic testing of pregnant women may be a cost-effective strategy.

The Human Herpes Virus 8-Encoded Chemokine Receptor Is Required for Angioproliferation in a Murine Model of Kaposi's Sarcoma.

Kaposi's sarcoma (KS)-associated herpes simplex virus or human herpes simplex virus 8 is considered the etiological agent of KS, a highly vascularized neoplasm that is the most common tumor affecting HIV/AIDS patients. The KS-associated herpes simplex virus/human herpes simplex virus 8 open reading frame 74 encodes a constitutively active G protein-coupled receptor known as vGPCR that binds CXC chemokines with high affinity. In this study, we show that conditional transgenic expression of vGPCR by cells of endothelial origin triggers an angiogenic program in vivo, leading to development of an angioproliferative disease that resembles KS. This angiogenic program consists partly in the expression of the angiogenic factors placental growth factor, platelet-derived growth factor B, and inducible NO synthase by the vGPCR-expressing cells. Finally, we show that continued vGPCR expression is essential for progression of the KS-like phenotype and that down-regulation of vGPCR expression results in reduced expression of angiogenic factors and regression of the lesions. Together, these findings implicate vGPCR as a key element in KS pathogenesis and suggest that strategies to block its function may represent a novel approach for the treatment of KS.