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Diminished Interferon-v and Lymphocyte Proliferation in Neonatal and Postpartum Primary Herpes Simplex Virus Infection Sandra K. Burchett, Lawrence Corey, Kathleen M. Mohan, Judith Westall, Rhoda Ashley, and Christopher B. Wilson

Departments of Pediatrics, Laboratory Medicine, Medicine, and Immunology, University of Washington and Children's Hospital and Medical Center, Seattle

Although primary herpes simplex virus (HSV) infection is generally self-limited in the immunocompetent host [ I], neonates and parturient women can experience severe morbidity or die [2-4]. Cellular immunity plays an important role in control of infection due to herpes group viruses [5, 6]. Accordingly, we compared the longitudinal development of HSV antigen-specific cellular immunity in neonates, postpartum women, and nonparturient adults with primary HSV infection. As indices of cellular immunity, we assessed lymphocyte proliferation and the production of two cytokines, interferon (IFN)-1' and tumor necrosis factor (TNF)-a, that have direct and indirect antiviral activity against HSV [712]. We found that during the initial period of primary HSV infection, at which time the virus can infect the central nervous system or other organ systems, HSV-stimulated lymphocyte proliferation and IFN-1' production were consistently lower in the neonates than in the nonparturient adults; results similar to those in the neonates were obtained in the three postpartum women with primary infection. Severe disease occurred only among the neonates and postpartum

Received 30 May 1991; revised IS January 1992. Grant support: National Institutes of Health (HO-07233 to S.K.B., HO18184 and AI-00568 to C.B.W., and AI-2038I to L.C.); United Cerebral Palsy (to C.B.W.). Reprints or correspondence: Dr. Sandra K. Burchett, Children's Hospital and Medical Center, P.O. Box C-5371, 4800 Sand Point Way N.E., Seattle, WA 98105.

The Journal of Infectious Diseases 1992;165:813-8 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6505-0004$01.00

women, groups in which the development of these antigenspecific cellular immune responses were delayed.

Methods Infant populations. We studied all infants suspected of having neonatal HSV infection at Children's Hospital and Medical Center between September 1983 and March 1988. Of these 35 neonates, 22 subsequently had culture-confirmed HSV infection (7 with type 1 [HSV-l], 15 with type 2 [HSV-2]). Twentyone of these infants were of term gestation and two were premature. HSV-infected neonates were classified according to the National Institute of Allergy and Infectious Disease collaborative neonatal herpes simplex infection study group into those with disseminated, central nervous system (CNS), or localized skin, eye, or mucocutaneous (SEM) HSV infection [13]. The neonates were treated, 30 rug/kg/day, with either acyclovir or adenine arabinoside (vidarabine) for 10 days. The clinical outcome of these patients has been reported elsewhere [14]. Briefly, of the 7 HSV-I-infected infants, 6 survived without morbidity and the 1 with disseminated disease died. However 10 of the 15 infants with HSV-2 infection experienced morbidity (usually neurodevelopmental delay) apparent within 6 months of age, and 1 infant with congenital infection died at age 4 weeks and was excluded from analysis. Of the 21 remaining infants, 8 were assessed only for antibodies to HSV. The other 13 (5 with HSV1, 8 with HSV-2) were available for study of their cellular immune responses and antibody status within the first 3 weeks after onset of infection and subsequently. Of these 13 infants, the mean time from onset of symptoms to initial study time point was 7.6 days (range, 1-17) and the mean age at the time of study initiation was 15.6 days (range, 5-34). Infants had peripheral blood for HSV antibody and cellular

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Interferon (IFN)-1' and tumor necrosis factor (TNF)-a production and lymphocyte proliferation in response to herpes simplex virus (HSV) antigen were assessed in 13 neonates and 3 parturient women with primary HSV infection. In comparison with 9 nonparturient adults, the neonates and parturient women showed significantly (P < .01) diminished HSV antigen-stimulated lymphocyte proliferation and IFN-1' production in the first 3-6 weeks after onset of infection. TNFa production did not differ significantly among HSV-infected groups. The impairment in neonatal cellular immunity was due, at least in part, to a specific deficit in response to HSV antigen. Lymphocyte proliferation and TNFa production in response to the mitogen concanavalin A (ConA) were comparable in adults and infants, but ConA-stimulated IFN-1' production in infants was diminished throughout the study period. In contrast, HSV antigen-stimulated IFN-1' production was comparable in infants and adults after 6 weeks. Not all patients with diminished cellular immune responses to HSV antigen manifested severe clinical disease. Nevertheless, patients with significant clinical morbidity had diminished cellular immune responses to HSV antigen. These results suggest that delayed acquisition of antigen-specific cellular immunity in primary HSV infection predisposes to more severe clinical disease.

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of the cells in all preparations were viable by trypan blue exclusion. Lymphocyteproliferation, IFN-"{, and TNFa assays The cell suspension (200 JLI) was incubated for 96 h in microtiter plates containing triplicate wells of medium alone, 25 JLg/ml mitogen concanavalin A (ConA), or inactivated HSV antigen (104 pfu/ ml); then [3H]thymidine was added and samples were harvested 24 h later as described [18]. The difference in counts per minute (cpm) was defined as the difference between the cpm of ConAor HSV-stimulated cells and the cpm of unstimulated (medium alone) cells. HSV antigen preparations consisted ofUV light-inactivated whole virion MS-2 strain ofHSV-2 from tissue culture supernatants. Cellular responses to this preparation in adults and neonates with HSV-I or -2 infection were similar. IFN-"{ and TNFa assays were done on supernatants from cells incubated for 72 or 120 h in 15 ml conical polystyrene tubes with medium alone, ConA, or HSV and were frozen at -70°C until they were assayed. Supernatants from both time points were assayed, and that with the highest value was used for analysis; the highest activity for IFN-"{ was usually at 120 h and for TNFa, 72 h. IFN-"{ was determined by RIA normalized to the National Institutes of Health standard of IFN-"{ as previously described [19]. TNFa was assayed by cytolysis of L-929 fibroblasts; the activity that was neutralized by monoclonal antibody to TNFa (provided by Genentech, South San Francisco) was normalized to a standard of TNFa as previously described [20]. The conditions used were determined to be optimal in initial experiments. Among the 13 control infants, the mean lymphocyte proliferation response to HSV antigen in the first 30 days of life was 389 cpm (HSV antigen cpm - unstimulated cpm). The mean amounts of IFN-"{ and TNFa produced at the same interval were 2 and 3 units/ml, respectively. We designated values > 1300 difference in cpm, > 12 units/ml IFN-"{, and > 12.5 units/ml TNFa (mean of controls + 2 SD) as evidence ofpositive responses in the lymphocyte proliferation and cytokine production assays. Statisticalanalysis. Data are depicted in figure I as individual patient values. The significance of differences between groups was determined using the Mann-Whitney U test. Because we were unable to detect differences in the magnitude and age-related development of the infants' responses by virus type (HSV -I vs. -2), disease localization (SEM vs. CNS), or treatment (acyclovir vs. vidarabine), data from all HSV-infected infants were pooled for analyses. The data for adults with HSV-l or -2 were also similar and were pooled.

Results Infant responses to HSV. None of8 HSV-infected infants studied in the first 10 days of symptomatic infection had a positive in vitro lymphocyte proliferation response to HSV antigen (figure I, top left). One of 8 HSV-infected neonates had positive IFN-"{ production (figure I, middle left), and none of 6 had positive TNFa production (figure 1, lower left) in response to HSV antigen. At this interval the mean values for antigen-stimulated lymphocyte proliferation, IFN-

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immune studies taken at enrollment and at the end of the 10day therapeutic course. Infants were subsequently reevaluated one or more times as outpatients between 6 weeks and 6 months after onset of symptoms. The 13 control infants did not have HSV isolated from mucosal sites or spinal fluid and on follow-up at age 12 months showed no serologic evidence of neonatal HSV infection. Of the 13 controls, 11 were diagnosed with a variety of illnesses that initially resembled HSV infection: an enteroviral illness (8), staphylococcal skin infection (2), and idiopathic oral ulcers ( I); 2 were clinically well but were exposed in the peripartum period to HSV. Adult populations. Two adult groups were studied. Twelve adults (9 female) who experienced clinically symptomatic culture-proven genital HSV infection (4 with HSV-1, 8 with HSV2) were studied within the first 3 days of symptom onset (mean, 1.5). All lacked antibodies to HSV-l and -2 at entry and seroconverted to the infecting HSV type on follow-up, so were defined as having primary HSV infection. This group was studied at intervals similar to those ofthe infants (i.e., onset ofinfection, at 3 and 6 weeks, and at 6 months). Three women were pregnant and delivered infants within 3 days of symptom onset. The babies were delivered at or the mothers were referred to the University of Washington, where genital cultures for HSV are obtained from all women presenting to the delivery suite [15]. During the years of this study, only one additional mother with primary HSV infection at delivery was identified. Her infant developed disseminated HSV-1 infection and died, so this mother and infant were not available for study. Of the studied pairs, two mothers had primary HSV-I infection and both infants developed SEM disease. A third mother experienced hepatitis and disseminated intravascular coagulation resulting from primary HSV-2 infection. Both the mother and her vaginally delivered baby received intravenous acyclovir for 10 days. The baby was not infected and served as a control infant in our study. Of the 9 nonparturient patients in the primary infection group, all received 200 mg ofacyclovir orally five times a day for 10 days from the first study visit and all had self-limited disease. The second adult group consisted of 13 HSV-seropositive parturient women who delivered infants either with neonatal HSV infection or who manifested symptoms consistent with HSV infection. This group represents the parturient women with recurrent infection, and their infants constituted our HSV-infected study infants and control infants. Three HSV-seronegative adults served as negative adult controls. Viralstudies. HSV was isolated in human diploid fibroblasts and typed by direct immunofluorescence using mouse monoclonal antibodies as previously described [16]. Antibodies to HSV were determined by Western blot analysis [17]. All sequentially collected sera from each mother/infant pair were assessed on blots derived from a single gel; HSV antibody specificity was defined as previously described [17]. Cellpreparations. Peripheral blood mononuclear cells were separated [ 18] by ficoll-hypaque density gradient centrifugation, washed twice in Hanks' balanced salt solution, and resuspended at 2 X 106 cells/ml in RPMI 1640 containing 2 mM t-glutamine, 25 mMHEPES buffer, 50 units/ml penicillin G, 50 ~g/ml streptomycin, and 10% human type AB serum. More than 95%

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Days from onset of symptoms 1', and TNFa of the HSV-infected infant group did not differ significantly from those of the infant control group. By 1120 days after the onset of symptomatic HSV infection, 50f9 infected infants had developed a positive lymphocyte proliferation response to HSV antigen (P < .05 compared with HSV-infected infants in the first 10 days after onset of illness and to infant controls), but only 3 of 9 HSV-infected infants had a positive IFN-1' production response to HSV antigen at this time. By 6 weeks after onset, all of the HSV-infected infants had developed a positive HSV antigen-stimulated lymphocyte proliferation response and all but one a positive

IFN-1' production response. Production of TNFa by cells from HSV-infected infants was significantly (P < .05) greater than that by cells from control infants ~3 weeks after onset of symptoms but not before. None of the 13 control infants or the 3 seronegative control adults had positive responses in any of these assays. Comparison with adult responses to HSV. In marked contrast to the HSV-infected infants' cells (figure I, top), those from most of the nine nonparturient adults with primary genital HSV infection exhibited positive lymphocyte proliferation and IFN-1' responses in the first 10 days after onset of

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Figure 1. Cellular immune responses to herpes simplex virus (HSV) antigen and to concanavalin A (ConA) mitogen in HSV-infected patients. e, HSV-infected infants; 0, parturient women with primary HSV infection; A, nonparturient adults with primary HSV infection; 6., parturient women with recurrent HSV infection. Left, responses to HSV antigen; right, responses to ConA mitogen. Shaded areas represent mean + 2 SO of control infant values for each parameter. Results outside shaded area are considered positive. Top row depicts lymphocyte proliferation as difference in counts per minute (stimulated cpm - unstimulated cpm); middle row depicts interferon (IFN)-,), production; bottom row depicts tumor necrosis factor (TNF )-a production.

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developed in one of three infants who had a positive IFN-1' response in the first 20 days after onset of infection and in one of six infants who did not. However, the number of infants studied is too small to formally exclude an association between the magnitude of the early cellular immune responses and subsequent outcome. It is important to note that severe HSV disease was seen only in individuals from the two groups (i.e., neonates and parturients) who had diminished HSV antigen-specific cellular immune responses compared with non parturient adults in the first 3 weeks after onset of primary HSV infection. To determine if the presence or absence of passively acquired antibody to HSV might be an additional predictor of outcome, Western blot analysis of samples from mother/ baby pairs was done at presentation. Four infants infected with HSV-I had no detectable antibody to HSV at presentation; the other 3 had HSV-I antibody. Of the 15 infants infected with HSV-2, 1 had SEM disease, 13 had CNS disease, and I had disseminated disease and died, yet each had passively acquired antibody to HSV-1 and 9 also had antibody to HSV-2. Thus the presence ofpassively derived HSV-2-specific antibody as determined by Western blot was not predictive of milder initial disease severity.

Discussion We observed a delay in the development ofHSV antigenspecific lymphocyte proliferation and IFN-1' production in HSV-infected neonates compared with nonparturient adults with primary genital HSV infection. These responses matured by 3 and 6 weeks after symptom onset, at which time they approximated the responses of nonparturient adults. However, it is during the first weeks of infection that HSV has the potential to produce severe disease in the neonate [2, 21]. Others have also found diminished HSV antigen-specific lymphocyte proliferation in the neonatal period [6, 2224]. However, the current study is the first to measure cytokine production and to compare longitudinally neonatal or infant responses to an adult control group with primary HSV infection. Each of the three pregnant women with primary genital HSV infection acquired just before parturition had a delay in the development of lymphocyte proliferation and IFN-1' production in response to HSV, similar to that seen in neonates. Although the parturient women with primary infection studied are too few to conclude that they are representative of pregnant and postpartum women as a whole, the findings in this group suggest that delayed acquisition of HSV antigen-specific responses may not be restricted to neonates. These findings do correlate with the increased incidence of severe HSV disease in pregnant women with primary genital infection [3, 4]. This is illustrated by the development of hepatitis and disseminated intravascular coagulation in one of our three parturient subjects who had primary infection with HSV-2. While TNFa was specifically

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symptoms, and all responded within the first 3 weeks. The responses by infected adults' cells in both assays were significantly greater (P < .0 I) than those by infected infants' cells or by controls' cells at both intervals in the first 3 weeks. Thereafter, HSV-stimulated lymphocyte .proliferation by cells from HSV-infected neonates was comparable to that of cells from infected adults with primary or recurrent genital infection. Production ofIFN-1' by cells from infected infants first became comparable to that by cells from infected adults at 6 weeks after onset. Only three parturient women with primary genital HSV infection were available for study, but none had a positive lymphocyte proliferation or IFN-1' production response to HSV antigen within the first 3 weeks after onset ofsymptoms. Like the infants, all three parturient women with primary genital HSV developed positive lymphocyte proliferation and IFN-1' responses by 6 weeks to 6 months after symptom onset. In contrast, all six parturient women with recurrent genital HSV infection had positive lymphocyte proliferation and IFN-1' responses in the first 3 weeks after delivery of their HSV-infected infant. TNFa production did not differ significantly among any of the HSV-infected groups at any time after onset of symptoms (figure I, lower left). However, cells from three of the nonparturient adults with primary HSV infection produced >350 units of TN Fa, >IO-fold that of the maximal production by cells from infants or parturient women with primary infection. Responses to ConA. The delay in the development of an HSV antigen-specific response in the infected neonates compared with nonparturient adults with primary HSV infection did not reflect a general impairment in cellular immunity. Lymphocyte proliferation and TNFa production after mitogen (ConA) stimulation were similar between HSV-infected infants and adults (figure I, top and bottom right) and their respective controls (not shown). However, at all intervals ConA-stimulated IFN-1' production by cells ofthe HSVinfected infants (figure I, middle left) was significantly less (P < .05) than that by cells from either adult group. Diminished IFN-1' production in response to ConA was also seen in the control infants compared with infected or control adults, as previously reported for this and other mitogens [19]. Correlates with clinical severity. Compared with responses in non parturient adults, HSV antigen-specific cellular immune responses in the first 3 weeks after onset ofsymptoms were universally diminished in the neonates and the parturient women with primary HSV infection. Among the individuals in these two groups, the magnitude of the IFN-1' or lymphocyte proliferation response in the first 3 weeks after onset was not predictive of clinical sequelae. For example, moderate to severe sequelae developed in one of five infants who had a positive lymphocyte proliferation response in the first 20 days after onset of infection and in one of four infants who did not. Similarly, moderate to severe sequelae

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tection in this case is dependent on the intrinsic production ofIFN-l' by adult cells. Similarly, Langford et al. [36] demonstrated that the antiviral effect of neutralizing antibody to HSV is augmented by IFN-l'. Thus, diminished IFN-l' production in neonates and parturient women in the initial weeks of primary HSV infection may directly contribute to the increased severity of clinical disease. In addition to antigen-specific immune responses, nonspecific immune effector mechanisms are believed to play a role in host defense to HSV, particularly in the early containment phase of infection [6]. In this regard, the finding by Kohl et al. [37] that mononuclear cells from neonates and postpartum women have diminished NK cell cytotoxicityto HSV-infected targets, compared with cells from nonparturient adults, suggests that combined deficits in antigen-specific and nonspecific cellular immunity to HSV are present in these groups. Our data show impairment in the early development of a primary T cell immune response to HSV in the neonates and mothers with primary HSV infection studied near the time of parturition. This impairment temporally parallels the potential for greater disease severity in these patients [2-4, 21]. The magnitude of the delayed HSV-stimulated lymphocyte proliferation and IFN-l' production did not correlate in individuals with the subsequent severity ofHSV disease, perhaps due to differences in other determinants [38], including the infecting viral type [14], extent ofviral exposure, and disease duration before initiation of antiviral therapy [39]. The protective role of passively derived, maternal antibody is not fully defined [21-23, 40, 41]. The presence ofmaternal antibody as detected by Western blot did not correlate with decreased disease severity in the neonates we studied. However, we did not assay for antibodies to HSV that mediate antibody-dependent cell-mediated cytotoxicity, the presence ofwhich has recently been shown to correlate with lower risk for disseminated disease [41]. Nevertheless, all nonparturient adults with primary HSV infection had early cell-mediated immune responses and self-limited disease, even though they lacked HSV antibodies at presentation. The results suggest that a delay in development of antigen-specific cellular immune responses may be necessary but not sufficient for the development of severe HSV disease. In summary, in our study neonates and mothers with primary HSV infection acquired near term gestation had diminished antigen-specific cellular responses during the first 3-6 weeks after delivery. This is a critical interval during which host defenses either act to limit disease, as in nonparturient adults, or, if inadequate, may permit progressive disease with resultant severe consequences, as in neonates. Whether immunotherapeutic agents, such as IFN-l', immunoglobulin preparations containing targeted antibody, or both, might be useful as adjuncts to current chemotherapeutic regimens for the treatment of neonatal HSV infection remains to be determined.

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produced in response to HSV stimulation, we did not detect significant differences between infected groups; this may be due in part to wide variability in TNFa production by cells from nonparturient adults with primary HSV infection. There are several potential explanations for diminished HSV antigen-stimulated cellular immune responses in the neonates and parturient women with primary HSV infection. Because neonates have a low frequency of HSV antigen-responsive precursor cells, it may require longer after infection for their numbers to increase sufficiently to produce a detectable response [25]. In addition, neonatal cells have a diminished capacity to produce IFN-l' in response to a wide variety of stimuli [19, 26, 27]. This is due primarily to decreased transcription of the IFN-l' gene and may reflect the absence of a memory lymphocyte subset that produces IFN-l' in high amounts [28-30]. If the decreased production of IFN-l' by neonatal T cells reflects in part the absence of memory T cells, then once a detectable antigen-specific T cell response develops (e.g., lymphocyte proliferation), one would predict that antigen-induced IFN-l' secretion would soon approximate that of adult T cells responding to the same antigen. This was the case in the HSV-infected neonates we studied. To our knowledge, HSV antigen-responsive precursor cell frequency or memory T cell numbers have not been determined for pregnant women. However, antigen-specific T cell responses [4,31], CD4+ T cell numbers, and T cell CD4-toCD8 ratios all may be diminished in pregnancy, with the lowest levels near term gestation [32]. Although pregnancyrelated hormonal factors may affect T cell function in vivo [4], in our studies cells were cultured in serum from nonpregnant adults, making it unlikely that results were due to an in vitro hormonal effect. Patients receiving acyclovir may have an attenuated lymphocyte proliferative response to HSV antigen [33]. However, this also is unlikely to be a major factor in the differences we observed, as (1) there were no cellular response differences between the vidarabine- versus acyclovir-treated infants, (2) the responses of the two untreated parturient women with primary HSV infection were delayed, and (3) all nine nonparturient adults with primary HSV infection received acyclovir yet showed the prompt development oflymphocyte responses~ Similarly, no differences were observed in cellular responses between infants or adults infected with HSV-l or -2. IFN-l' appears to be an important component ofHSV antigen-specific cellular immunity. In adults, Torseth and Merigan [34] showed that the magnitude of HSV antigenspecific IFN-l' production in vivo and in vitro correlates with a longer interval to recurrence of HSV infection. Kohl [35] recently found that IFN-l' is the only cytokine that confers on human neonatal blood mononuclear cells the capacity to protect neonatal mice from lethal HSV infection. In contrast, mononuclear cells from adults confer protection when given along with other cytokines, such as interleukin-2; pro-

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Diminished interferon-gamma and lymphocyte proliferation in neonatal and postpartum primary herpes simplex virus infection.

Interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha production and lymphocyte proliferation in response to herpes simplex virus (HSV) antigen...
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