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J Dent Res 81(6): 416-421, 2002
© 2002 International and American Associations for Dental Research

RESEARCH REPORT
Clinical

Salivary Defense Factors in Herpes Simplex Virus Infection

H. Välimaa1,2,*, M. Waris3, V. Hukkanen2, M.F.J. Blankenvoorde4,5, A.V. Nieuw Amerongen4, and J. Tenovuo1

1 Department of Cariology, Institute of Dentistry,
2 Department of Virology,
3 Laboratory of Biophysics, Institute of Biomedicine, University of Turku, Turku, Finland;
4 Department of Oral Biochemistry, ACTA, Amsterdam, the Netherlands; and
5 currently at Aventis Pharma, Medical Department, Hoevelaken, the Netherlands;

*corresponding author, hannamari.valimaa{at}utu.fi


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Saliva may contribute to a lowering of the infectious herpes simplex virus (HSV) dose during transmission and consequently abrogate infection or lead to decreased reactivation. To test this hypothesis, we assayed saliva for innate defense factors, immunoglobulin content, and the capacity to interfere with HSV infection. Serum or salivary anti-HSV IgG levels did not correlate with control of recurrent labial herpes (RLH) and were significantly higher in subjects with RLH compared with asymptomatic seropositive subjects. Although no differences in levels or output rate of innate defense factors between the groups were observed, the salivary neutralizing activity correlated with lactoferrin and hypothiocyanite concentrations in the asymptomatic seropositive group. Our results suggest that saliva contains factors, in addition to anti-HSV immunoglobulins, that neutralize HSV and may indirectly contribute to the control of RLH.

KEY WORDS: saliva • defense • innate • HSV


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The HSV life cycle has been well-characterized in humans. After primary infection of oro-facial mucosa or skin, the virus resides in a latent state in the neurons of the sensory ganglion of the affected region. Various stimuli may re-activate HSV in latently infected neurons. Following re-activation, the virus migrates via sensory nerves to the epithelium, where it replicates and, under favorable circumstances, causes visible lesions, also known as recurrent HSV.

Several alternative cell types have been suggested as origins of HSV excreted in the oral cavity. Oral epithelium and, more specifically, gingival sulcular epithelium (Zakay-Rones et al., 1973) and ocular and salivary tissues (Kaufman et al., 1967) have all been proposed as sites of HSV replication. Extra-oral persistence of HSV DNA in non-neuronal tissues has been demonstrated in skin (Brice et al., 1994), blood (Brice et al., 1994), and ocular tissue (Crouse et al., 1990).

The role of saliva in the control of intra-oral herpes simplex virus (HSV) infection is controversial, since HSV can be isolated from saliva of asymptomatic HSV seropositive individuals (Douglas and Couch, 1970; Spruance, 1984). The frequency of asymptomatic oral shedding of infectious HSV varies between 2 and 9% in healthy populations (Wheeler, 1988) and is even more frequent in immunocompromised subjects (38%) and in those undergoing oral surgery (20%) (Kameyama et al., 1988). Furthermore, the use of more sensitive methods, such as detection of HSV nucleic acid in saliva by PCR, has shown that HSV shedding is actually more frequent than was previously believed (Tateishi et al., 1994). Given the high frequency of HSV shedding in the absence of apparent disease, it seems likely that HSV may become inactivated to a certain level in the oral environment.

It is clear that, from time to time, infectious HSV is shed to whole saliva, even during asymptomatic periods. Although saliva contains several components that neutralize infectious HSV in vitro (Cisani et al., 1989; Björck et al., 1990; Hasegawa et al., 1994; Gu et al., 1995; Mikola et al., 1995), the role of saliva in horizontal transmission and in the control of re-activations of HSV in vivo is unclear. During HSV transmission to mucosal surfaces, saliva may contribute to decreasing the initial infective viral dose, thereby leading to less frequent and more limited re-activations. This study was designed to investigate the possible clinical role of salivary defense factors in inactivation of oral HSV and in the control of re-activations.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects and Study Design
In total, 167 students were tested for serum anti-HSV IgG levels. Subjects participated in the study with informed consent. Of these, 88 (mean age, 25 yrs) participated in the actual study, which involved completing a questionnaire and donating a salivary sample. Subjects were asked whether they had ever experienced labial or genital herpes and the frequency of re-activation. Reporting labial herpes was considered reliable evidence of recurrent HSV infection.

The study was approved by the Ethics Committee of the Medical Faculty of Turku University.

Collection and Treatment of Saliva
Paraffin-stimulated whole saliva was collected in a volume of 15 mL. Subjects were asked to refrain from eating, drinking, or smoking for 1 hr prior to the collection. Salivary buffer capacity and hypothiocyanite concentration were measured immediately following sample collection. Lysozyme and lactoferrin concentrations were measured from aliquots directly frozen in -20°C without being processed. The reminder of the sample was first centrifuged at 20,000 g for 10 min at 4°C and stored at -20°C or -70°C.

Immunological Assays
Anti-HSV immunoglobulins were analyzed by enzyme-linked immunosorbent assay with the use of HSV envelope antigen prepared from HSV type 1 strain VR (Martin et al., 1972). This antigen detects both anti-HSV-1 and -2 antibodies. The results were read as arbitrary units by application of the standard curve method (Koskinen et al., 1987).

For testing anti-HSV salivary immunoglobulins, we diluted saliva from 1:2 to 1:256 in two-fold dilutions. The result was read as an end-point titer which was defined as the dilution at which the absorbance of the sample was 3 SD units from the mean of saliva samples of HSV-seronegative subjects.

Determination of total salivary IgA, IgG, and IgM concentrations was performed as previously described (Kirstilä et al., 1996).

Cell-protective Assay and Neutralizing Effect of Saliva on HSV-1
In the cell-protective assay, confluent African green monkey kidney cells (Vero) on 24-well plates were overlaid with 1:2 dilutions of saliva. After overnight incubation, cells were washed twice and infected by centrifugation with 100 plaque-forming units (PFU) of HSV-1 (strain F). After 20 hrs, infected cells were detected microscopically by immunoperoxidase staining (Ziegler et al., 1988). The PFU of the cultures were counted, and the results between groups were compared. We studied the neutralizing effect of saliva by incubating saliva with 200 PFU of HSV-1 for 30 min at 37°C. Subsequently, Vero cells were inoculated with the mixture diluted 1:10 with culture medium, and the infected cells were detected as described above. Sterile PBS mixed with HSV-1 was used as a control. The neutralization capacity was expressed as 100% - (%PFU of the sample/PFU of the control).

Chemical Assays
For the measurement of total protein content of saliva, a colorimetric method involving the Folin phenol reagent was used (Lowry et al., 1951). Buffer capacity, the concentrations of hypothiocyanite, thiocyanate, lactoferrin, and lysozyme, as well as the activities of salivary peroxides and myeloperoxidase were determined as described by Kirstilä et al. (1996). Mucin/MG2 activity was quantified according to Bolscher et al. (1999). Cystatin S concentration and cystatin and {alpha}-amylase activities were defined as described by Henskens et al. (1996).

Statistical Analyses
The data were analyzed with non-parametric Kruskal-Wallis and Mann-Whitney U-tests. Spearman rank correlations were calculated for defense factors and protective or neutralizing activity of saliva. Two-sided p-values of less than 0.05 were considered statistically significant. Statistical analyses were carried out with StatView 4.02 (Abacus Concepts, Inc., Berkeley, CA, USA). Data are presented as medians (ranges).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Among 167 subjects initially tested, the prevalence for serum anti-HSV IgG antibodies was 39.5%. The final study population consisted of 30 serum anti-HSV IgG positive subjects with recurrent labial herpes (RLH) and 18 subjects with serum anti-HSV IgG but no recurrences. Forty subjects were serum anti-HSV IgG negative with no RLH.

Serum anti-HSV IgG levels were significantly higher (p = 0.0005) in subjects with RLH (49.7 arbitrary units; 9.4-83.8) than in asymptomatic serum anti-HSV IgG positive subjects (16.1 arbitrary units; 8.2-81.1) (Fig. 1aGo). The frequency of annual re-activations reported by subjects showed no relationship to serum (rs = -0.049, p = 0.80) or salivary (rs = 0.044, p = 0.82) anti-HSV IgG levels or other defense factors studied.



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  		Figure 1. Anti-HSV immunoglobulins in serum and saliva. Recurrent labial herpes (RLH). (a) Anti-HSV IgG levels in sera were significantly higher (p = 0.0005; Mann-Whitney U-test) in HSV-seropositive subjects with recurrent labial herpes than in asymptomatic seropositive subjects. (b) Anti-HSV IgA levels in saliva were low in all groups, whereas anti-HSV IgG levels were clearly detectable in both HSV-seropositive groups. There was a clear difference (p = 0.042; Mann-Whitney U-test) in the levels of salivary anti-HSV IgG between subjects with and those without recurrent labial herpes (endpoint titer ± SE).

 
Salivary anti-HSV IgG levels clearly classified the subjects into HSV-seronegative and -seropositive groups (Fig. 1bGo). The difference in the salivary anti-HSV IgG titer between the two seropositive groups was lower (p = 0.042) than that discovered in serum (p = 0.0005), and there was no correlation between serum and salivary anti-HSV IgG levels in either seropositive group (rs = 0.14, p = 0.34). Salivary anti-HSV IgA levels were low in all groups (Fig. 1bGo). With the exception of one subject, anti-HSV IgM could not be detected in the saliva samples.

No difference in the cell-protective activity of saliva could be detected between the groups (data not shown), but in all, the application of saliva onto the cells before the infection resulted in an average 50 to 60% reduction in PFU values in the cultures (Fig. 2aGo).



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  		Figure 2. Cell-protective and neutralization assays. Recurrent labial herpes (RLH). (a) There were no differences in the cell-protective activity of saliva between the groups. Saliva applied before infection reduced the number of plaque-forming units (PFU) detected in cell cultures by an average of 50 to 60%. The cultures were infected with 100 PFU, and the numbers of PFU detected in the cultures are illustrated. (b) Saliva of asymptomatic HSV-seropositive subjects neutralized HSV more efficiently than saliva of subjects with recurrences (p = 0.05; Mann-Whitney U-test). The percent of neutralization is illustrated.

 
Saliva of HSV-seropositive subjects with no history of RLH possessed significantly higher (p = 0.05) HSV-neutralizing capacity (67.8%; 41.3-86.4) than did saliva of subjects with RLH (56.4%; 16.9-96.9). The difference was not significant when these two groups were compared separately or together with the group of HSV-seronegative subjects (61.1%; 2.9-96.9) (Fig. 2bGo). None of the investigated defense factors correlated with salivary neutralization capacity if all subjects were included. Instead, in the group of HSV-seropositive subjects without RLH, there was a positive correlation with lactoferrin (rs = 0.54, p = 0.026) and a tendency for correlation with hypothiocyanite (rs = 0.43, p = 0.094) concentrations, whereas no correlation with serum (rs = 0.082, p = 0.74) or salivary (rs = 0.32, p = 0.19) anti-HSV IgG could be detected. No significant correlations were detected within the other two groups.

The three groups did not differ from each other with respect to salivary buffer capacity or salivary flow rate (Table 1Go). No significant differences among the groups could be discovered in the concentrations or secretion rates of total salivary protein or innate salivary defense factors (Table 1Go). When the two HSV-seropositive groups were combined and compared with HSV-seronegative subjects, no significant differences were discovered between the groups in salivary buffer capacity, flow rate, or in the concentrations and secretion rates of salivary protein and innate defense factors. However, a trend for slower secretion rate of {alpha}-amylase with HSV-seropositive subjects was observed (p = 0.095).


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  		Table 1. Concentrations or Activities and Secretion Rates of Studied Salivary Properties or Constituents
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the current study, we have investigated the role of salivary defense factors in regulating the establishment of initial HSV infection and the re-activation of virus from latency. Intra-oral HSV lesions occur at low frequency within the population, and HSV etiology of these lesions requires virological verification if misdiagnosis is to be avoided (e.g., aphthae). Consequently, a sufficiently large study population with intra-oral HSV lesions would have been difficult to obtain. We hypothesized that high activity of oral defense factors would be associated with more limited primary HSV infection, resulting in lower viral load in the ganglia that would be observed clinically as fewer intra- or extra-oral re-activations. Therefore, we decided to study oral defense factors in subjects with and without recurrent labial herpes.

Although IgA is the predominant immunoglobulin class in saliva, salivary IgG has been considered to be responsible for most of the HSV-neutralizing activity in whole saliva (Douglas and Couch, 1970; Gyselink et al., 1978). Consistent with these previous studies, we observed that although total salivary IgA levels were higher than total salivary IgG levels in all groups (Table 1Go), most of the anti-HSV salivary antibodies were of the IgG isotype (Table 2Go). The low level of anti-HSV IgA in saliva made measurement of anti-HSV IgA unsuitable for reliable determination of HSV seropositivity. Instead, serum anti-HSV IgG positive subjects were all similarly positive for salivary anti-HSV IgG. Compared with asymptomatic seropositive subjects, the subjects with RLH had significantly higher levels of anti-HSV IgG in both serum and saliva (Table 2Go). However, the level of serum or salivary anti-HSV IgG did not correlate with the frequency of RLH. Interestingly, there was no correlation between the level of saliva and serum anti-HSV IgG antibody. This lack of correlation suggests that, in addition to passive filtration from the serum, an undescribed mechanism may exist for the transport of IgG through the oral mucosa.


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  		Table 2. Anti-HSV Immunoglobulins in Serum and Saliva

 
Previously, human saliva has been shown to be able to neutralize HSV (Gyselink et al., 1978; Bergey et al., 1993). In the current study, we compared the neutralizing activity of whole stimulated saliva on HSV infection from subjects of different HSV status. The saliva of asymptomatic HSV-seropositive subjects had higher HSV-neutralizing activity than did the saliva of subjects with RLH, suggesting that salivary defense factors may contribute to the control of RLH. However, the subjects with RLH had higher salivary anti-HSV IgG levels than the asymptomatic subjects. This observation indicates that salivary factors other than anti-HSV IgG are more important for neutralization of HSV in vitro, and suggests that these factors may also play a role in the control of RLH in vivo. Submandibular and sublingual saliva has been shown to possess greater HSV-neutralizing activity compared with parotid saliva (Bergey et al., 1993). Since the parotid gland secretes fewer cystatins and mucins compared with submandibular and sublingual glands, this finding suggests a significant role for these molecules in the inactivation of HSV. However, our results indicate that HSV-neutralizing activity was independent of the levels of both low-molecular-weight mucins and cystatins. In contrast, HSV-neutralizing activity did correlate with the level of lactoferrin and, to a lesser extent, of hypothiocyanite in the group of asymptomatic HSV-seropositive subjects. This correlation with lactoferrin and hypothiocyanite levels is consistent with the ability of lactoferrin to interfere with the early steps of in vitro HSV infection (Hasegawa et al., 1994), possibly by binding to the attachment receptor of HSV (heparan sulphate) and thereby blocking viral attachment to the oral mucosa, and with the oxidizing capacity of hypothiocyanite that has been shown previously to inactivate enveloped viruses (Pourtois et al., 1990; Mikola et al., 1995).

The application of saliva to cells before HSV inoculation resulted in significant levels of protection of the cells from infection that were comparable in all groups (Fig. 2aGo). A similar effect on HSV replication has been described in previous studies where unstimulated whole saliva (Heineman and Greenberg, 1980) and stimulated pure saliva from major salivary glands (Bergey et al., 1993) were used. Similar to our findings, Heineman and Greenberg (1980) observed that the cell-protective effect of saliva did not correlate with anti-HSV antibody level. However, in contrast to our results, they found the cell-protective activity to be higher in saliva of seropositive subjects without RLH compared with that in those with RLH. This disparity may be due to these authors' use of unstimulated saliva or our use of a more sensitive detection method for HSV. Heineman and Greenberg (1980) did not investigate other salivary defense factors, but in our study, the protective activity had no relation to any studied non-specific salivary defense factor.

HSV enters the oral cavity either by endogenous secretion of re-activated virus or by exogenous exposure. In either case, several components of immunity are involved in the defense of the body at mucosal surfaces. The individual contribution of each component in mediating the inactivation of HSV is difficult to assess, since defense mechanisms work in parallel and may interact in either an additive or synergistic manner (Lenander-Lumikari and Loimaranta, 2000). Our results suggest that factors other than anti-HSV immunoglobulins in saliva are important for neutralization of HSV and may also contribute to the control of RLH. In addition, these innate defense factors may play a role in preventing transmission of the virus to non-immune individuals and may explain the low frequency of HSV transmission via oral secretions.


   ACKNOWLEDGMENTS
 
We thank Ms. Aila Lähteenmäki, Ms. Katja Läpikivi, and Ms. Petra van den Keybus for expert technical assistance. We also thank Dr. Pekka Vilja (Tampere University, Finland) for his help with the lactoferrin assays. The study was supported financially by the Finnish Dental Society, the Finnish Cultural Foundation (Satakunta Foundation), and Turku University Central Hospital.

Received March 19, 2001; Last revision March 13, 2002; Accepted March 18, 2002


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 MATERIALS & METHODS
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 DISCUSSION
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