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Psychosomatic Medicine 62:828-837 (2000)
© 2000 American Psychosomatic Society

ORIGINAL ARTICLES

Reductions in Herpes Simplex Virus Type 2 Antibody Titers After Cognitive Behavioral Stress Management and Relationships With Neuroendocrine Function, Relaxation Skills, and Social Support in HIV-Positive Men

Stacy Cruess, PhD, Michael Antoni, PhD, Dean Cruess, PhD, Mary Ann Fletcher, PhD, Gail Ironson, MD, PhD, Mahendra Kumar, PhD, Susan Lutgendorf, PhD, Adele Hayes, PhD, Nancy Klimas, MD and Neil Schneiderman, PhD

From the Departments of Psychology (S.C., M.A., D.C., G.I., M.K., A.H., N.S.), Psychiatry and Behavioral Sciences (M.A., G.I., M.K., N.S.), Medicine (M.A.F., N.K., N.S.), and Biomedical Engineering (N.S.), University of Miami, Miami, FL; and the Department of Psychology (S.L.), University of Iowa, Iowa City, IA.

Address reprint requests to: Michael H. Antoni, PhD, Department of Psychology, University of Miami, Merrick 212, Coral Gables, FL 33124-2070. Email: mantoni{at}umiami.ir.miami.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
OBJECTIVE: Coinfection with herpes simplex virus type 2 (HSV-2) is common in individuals infected with human immunodeficiency virus (HIV) and may have health implications. This study examined the effect of a 10-week cognitive behavioral stress management (CBSM) intervention on immunoglobulin G (IgG) antibody titers to HSV-2 in a group of mildly symptomatic HIV-infected gay men and the degree to which these effects were mediated by psychosocial and endocrine changes during the 10-week period.

METHODS: Sixty-two HIV+ gay men were randomly assigned to either a 10-week CBSM intervention (N = 41) or a wait-list control condition (N = 21). Anxious mood, social support, cortisol/dehydroepiandrosterone sulfate (DHEA-S) ratio levels, and HSV-2 IgG antibody titers were assessed at baseline and after the 10-week period. CBSM participants also recorded their stress levels before and after at-home relaxation practice.

RESULTS: HSV-2 IgG titers were significantly reduced in the CBSM participants but remained unchanged in the control group after the 10-week intervention period. Increases in one type of social support, perceived receipt of guidance, during the 10 weeks was associated with and partially mediated the effect of the intervention on HSV-2 IgG. Similarly, decreases in cortisol/DHEA-S ratio levels were associated with decreases in HSV-2 IgG, and lower mean stress levels achieved after home relaxation practice were associated with greater decreases in HSV-2 IgG among CBSM participants.

CONCLUSIONS: These findings suggest that behavioral and psychosocial changes occurring during CBSM interventions, including relaxation, enhanced social support, and adrenal hormone reductions, may help to explain the effects of this form of stress management on immune indices such as HSV-2 antibody titers.

Key Words: herpes simplex virus • human immunodeficiency virus, • neuroendocrine • relaxation, • social support • stress management.

Abbreviations: ANOVA = analysis of variance; BMI = body mass index; CBSM = cognitive behavioral stress management; CDC = Centers for Disease Control and Prevention; DHEA = dehydroepiandrosterone; DHEA-S = dehydroepiandrosterone sulfate; DSM-III-R = Diagnostic and Statistical Manual of Mental Disorders, third edition revised; HIV = human immunodeficiency virus; HSV-2 = herpes simplex virus type 2; IgG = immunoglobulin G; MMSE = Mini-Mental State Examination; POMS = Profile of Mood States; SCID-II = Structured Clinical Interview for DSM-II; SCID-NP-HIV = Structured Clinical Interview for DSM-III-R–nonpatient version for HIV studies; SIGH-AD = Structured Interview Guide for the Hamilton Anxiety and Depression Scales; SPS = Social Provisions Scale; TMD = total mood disturbance.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
Several studies have suggested that the prevalence of HSV-2 is greater in individuals infected with HIV than in those not infected with HIV (1–4). Percentages of HIV-infected individuals also seropositive for HSV-2 range from 62 to 88% in various studies (1–4). One reason for this high concordance rate may be that HSV-2 acts as a risk factor for HIV transmission, perhaps even more so than other herpes viruses. Specifically, individuals may be more susceptible to HIV seroconversion if they have HSV-associated lesions that facilitate transmission of the virus from an infected sexual partner (5, 6). Similarly, one study suggests that HIV-1 virions in the host are likely to be present in HSV-2 lesions, thus making transmission of HIV to the uninfected partner more efficient (7).

In addition to increased risk of HIV transmission, there is another reason that coinfection with HSV-2 may be particularly significant for HIV-infected individuals. HSV-2 and HIV can simultaneously coinfect and replicate in the same cell (8). Furthermore, HSV-2 replication (8) and even just exposure to HSV-2 virions (9) may facilitate replication of HIV in vitro, which in turn may lead to faster disease progression. In addition, recurrent or persistent herpes simplex lesions, a commonly occurring CDC-defined category B symptom of HIV disease (10), can be a painful (11) and at times life-threatening (12) condition for HIV-infected individuals. Thus, for the high percentage of individuals infected with both viruses, suppression of HSV may have important implications for both immediate health status and quality of life as well as long-term HIV disease course and clinical outcomes.

Over the past two decades, there has been growing awareness of the bidirectional relationships among psychological factors, neuroendocrine agents, and immunologic processes that are relevant for the control of herpes viruses. Numerous studies have shown that stressors and psychological distress states are associated with clinical reactivation of different herpes viruses and increases in antibody titers specific to these viruses, which is suggestive of viral reactivation (13–19). Similar results have also been found in HIV-infected samples. For example, Robertson et al. (20) found that high levels of psychological distress were associated with higher levels of circulating HSV antibodies in HIV-infected men. Lutgendorf et al. (21) found that HIV+ men participating in a CBSM intervention had decreases in IgG antibody titers to HSV-2 that paralleled decreases in depressed mood.

Several more recent studies of CBSM in HIV-infected men have pointed to the importance of several other important changes that occur during the group intervention. For example, social support has long been identified as an important predictor of psychological well-being (22, 23). In an examination of the mediators of distress changes over the course of a CBSM intervention for HIV-infected men, Lutgendorf et al. (24) identified increases in two aspects of social support, guidance and reliable alliance, as an important predictor of distress reductions. Although social support has been related to immunologic status and disease progression in HIV-infected persons (25), no published study to date has examined the relationship of social support changes to immune changes such as reductions in HSV-2 antibody titers during a stress management intervention for HIV-infected men. Additionally, although the relationship of changes in depressed mood to HSV-2 antibody titer changes during CBSM has been examined (21), the relationship of anxious mood changes to this immune parameter has not been examined. Although the reactions of individuals to a diagnosis of HIV are highly variable, anxiety is commonly seen in individuals dealing with HIV, given the host of psychosocial stressors that often accompany infection with this virus (26). Several studies have also identified anxiety as a precipitating factor to recurrences of HSV in HIV-seronegative individuals (19, 27). It would be interesting to examine whether increased proficiency at reducing anxiety and bodily tension by means of stress management techniques such as relaxation are associated with reductions in HSV-2 titers among HIV+ individuals.

Another factor that has gained increased attention in relationship to HIV in recent years is gonadal hormones such as DHEA and its conjugated derivative, DHEA-S. Several correlational studies have found a relationship between low levels of DHEA and low CD4 counts in HIV-infected individuals (28, 29). DHEA has also been found to inhibit HIV replication (30, 31) and latent viral reactivation (32) in vitro and thus may have significant clinical implications for HIV disease progression. Recent work suggests that the interaction of DHEA with glucocorticoid activity may be particularly salient (33) because glucocorticoids have been shown to have immunosuppressive properties (34) and DHEA may act as a glucocorticoid antagonist (35, 36). The ratio of plasma levels of cortisol to DHEA-S has been examined in relationship to lean body mass in HIV-infected individuals (37) and more recently in a sample of HIV+ men assigned to either a CBSM intervention or wait-list control group (38). In the latter study, the researchers observed that participation in a CBSM group seemed to buffer against increases in the cortisol/DHEA-S ratio observed in the HIV-infected men assigned to the control group. Furthermore, increases in the cortisol/DHEA-S ratio were associated with increases in perceived stress. Given the recent implications of the role of DHEA in HIV infection and the known immunosuppressive properties of cortisol, it would be interesting to examine the relationship of the cortisol/DHEA-S ratio to changes in HSV-2 antibodies during a CBSM intervention for HIV-infected men.

The purpose of the study reported here was to examine the effect of participation in a CBSM group on changes in antibody titers to HSV-2 in a larger sample of HIV-infected gay men than has been studied to date. Furthermore, we sought to investigate whether changes in several other variables previously observed to change with CBSM intervention participation were related to changes in HSV-2 titers. Specifically, we examined changes in anxious mood and overall mood disturbance, several aspects of social support, proficiency at stress reduction through relaxation practice, and changes in cortisol/DHEA-S levels.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects
HIV+ men were recruited for a study of stress management and relaxation training primarily through flyers, physician referrals, referrals from previous participants, and HIV/AIDS service organizations. Participants were required to have at least an eighth grade education and the ability to read and write fluently in English. Participants were also required to have at least one non–AIDS-defining symptom or to have a CD4 count between 200 and 700 cells/mm3. Exclusion criteria were designed to increase the homogeneity of the sample and to reduce confounding factors that might affect the physiological and psychological dependent measures. The following exclusion criteria were selected: clinical diagnosis of AIDS at any time (10), CD4 cell count <200 cells/mm3 at screening, presence of risk factors for HIV transmission in addition to homosexuality, present or past intravenous drug use or transfusion before March 1985, chronic illness associated with persistent generalized lymphadenopathy or changes in the immune system, and a history of cigarette smoking >50 pack-years. We also excluded those experiencing an acute infection, changes in medications, or death of a lover or close friend in the past month. Similarly, we excluded those who had undergone surgery requiring general anesthesia within the past 3 months or who had started formal psychotherapeutic interventions or a formal aerobic fitness training program within the past 3 months. In addition, individuals with a current alcohol or nonintravenous substance dependency as determined by DSM-III-R criteria; a current major psychiatric disorder (eg, bipolar affective disorder, major depressive disorder with melancholia, and anxiety disorders other than adjustment disorders) as determined by the SCID-NP-HIV (39); a DSM-III-R axis II diagnosis of antisocial or borderline personality disorder as determined by the SCID-II; or a previous history of organic mental disorder, schizophrenia, or other major psychopathology were also excluded. SIGH-AD (40–42) depression (nonorganic) or HIV-corrected anxiety scores >15 were also exclusionary, as was the presence of cognitive deficits as evidenced by a score of <25 on the MMSE (43). Regular use of immunomodulator medications (eg, interferon or interleukin-2) within the last 3 months was also exclusionary. Use of such medications starting after the study began was monitored but not exclusionary. We did not exclude individuals taking low-dose neuroleptics, antidepressants, benzodiazepines, and antiretroviral medications, but we did monitor use of these agents.

Psychological Measures
Profile of Mood States
The POMS (44) is a 65-item checklist designed to assess mood over the past week. Respondents are asked to rate each adjective on a 5-point Likert scale ranging from 0 ("not at all") to 4 ("extremely"). The POMS has six individual mood subscales and one overall index of distress. The POMS subscales have been shown to have internal consistencies near or above 0.90 and test-retest reliabilities ranging from 0.65 to 0.74. Several studies have shown the POMS to have good predictive and construct validity (44). The POMS has also been used in previous studies of HIV-infected individuals and has been shown to be sensitive to stressor-related affective responses (24, 45). Because of our intent in monitoring changes in stress and anxiety, the POMS subscales of interest in the present study were the Anxiety and TMD subscales.

Social Provisions Scale
The SPS (46) is a 24-item self-report inventory designed to assess the extent to which an individual perceives his or her social relationships as providing opportunities to receive and give various types of emotional and instrumental social support. It is comprised of six subscales as well as a Total Social Provisions score. {alpha} reliability coefficients for the SPS subscales have been shown to be fair, ranging from 0.65 to 0.76, and the reliability of the Total Social Provisions score is 0.915. The SPS has also been shown to have good construct and discriminant validity. Furthermore, research on the SPS suggests that social support as measured by the SPS contributes unique variance in the explanation of psychological distress, health, and illness when investigated with other variables such as social desirability and intraversion-extraversion (46). The guidance and reliable alliance subscales of the SPS, which were used in our study, have been shown to be sensitive to changes in social support over the course of a 10-week CBSM intervention in HIV-infected gay men (24).

Relaxation Training Competence and Compliance
For subjects assigned to the 10-week CBSM condition, competence at reducing perceived stress through relaxation exercises and compliance with daily relaxation homework exercises was assessed by means of subject self-reporting. During the 10-week intervention period, subjects completed a card each day recording how many times they practiced the relaxation exercises that day and their perceived stress level before and after practice. Stress level was rated on a Likert scale ranging from 1 (lowest) to 7 (highest). Reduction in distress through relaxation exercises was computed as the mean {Delta} score for prerelaxation stress level and postrelaxation stress level. Relaxation compliance was assessed as the total number of times relaxation was practiced outside a session during the 10-week intervention.

Biobehavioral Control Variables
A number of variables shown to have potentially confounding effects on immune status were investigated as possible control variables (47). These included cigarette use, alcohol use, coffee consumption, aerobic exercise, and sleep. Cigarette use was assessed by the subject’s report of how many packs of cigarettes they smoked per day. Alcohol use was assessed as the number of alcoholic drinks consumed in the past week. Coffee consumption was measured as the number of cups of coffee typically drank per day. Aerobic exercise was assessed by asking subjects to report the number of hours spent exercising in the past week. Sleep was assessed as the average number of hours slept per night in the past week.

HSV-2 IgG Antibody Titers
Peripheral blood was collected from nonfasting participants by a phlebotomist between 8:00 AM and noon using sterile evacuated tubes containing sodium heparin (Vacutainer, catalog no. 6489, Becton-Dickinson, Rutherford, NJ). IgG antibodies to HSV-2 were assessed using the Clin-ELISA test kit and reagents supplied by Incstar (Stillwater, MN, 1993, kit nos. 4510 and 4512). Diluted serum samples were incubated with the virus. If antibodies to HSV-2 were present in the sample, antigen-antibody complexes (para-nitrophenylphosphate) were formed and then bound to anti-human IgG. Samples were then allowed to react with a conjugate solution, which results in color formation in the presence of virus-specific antibodies. Absorbance was directly related to the amount of virus antibodies present in the serum.

Total IgG level was used to control for nonspecific polyclonal B cell activation. Rate nephelometry (ICS Analyzer II, Beckman Instruments, Brea, CA) was used to assess IgG levels following a rate kinetic method outlined by Fritsche and DeLeon (48). Sera were diluted in a diluent buffer containing a nonionic detergent. Aliquots of diluted samples were placed in a cuvette containing a polyethylene glycol reactant buffer to increase reaction rate and decrease complex solubility. Next, monoclonal antibody to IgG was added, and the rate of complex formation was recorded. The antibody concentration was determined from the standard curve for each monoclonal antibody using the maximum rate.

Cortisol/DHEA-S Ratio
DHEA-S and cortisol were measured in plasma obtained from subjects during the early morning venipuncture described for HSV-2 antibody titers. Approximately 10 ml of blood was collected in tubes coated with ethylenediaminetetraacetic acid and centrifuged at 2500 rpm for 15 minutes at 4°C. Plasma was separated, aliquots were placed in appropriately labeled freezer tubes, and tubes were stored at -80°C until use. These samples were analyzed using radioimmunoassay competitive binding techniques as described elsewhere (49). Cortisol/DHEA-S ratios were expressed in nanomoles per liter.

Procedure
Potential participants first underwent a preliminary screening over the telephone to determine their initial eligibility. Participants who were not excluded on the basis of their telephone interview were invited to make an appointment to come to the study office for further assessment. The participant’s screening visit took 2 to 21/2 hours. Participants were first given several informed consent forms and were then briefed on the study and the day’s activities and given a chance to ask questions. They were then administered a standardized psychiatric interview by a predoctoral research assistant trained specifically in the administration of these interviews. The psychiatric assessment battery consisted of the SCID-NP-HIV (39), the SIGH-AD (40–42), and the MMSE (43). Participants were then given a physical examination by a registered nurse or physician and had their blood drawn to confirm that their CD4 cell count was >200 cells/mm3. Eligible participants were then given a psychosocial questionnaire to complete at home. Participants returned approximately 1 week later, pending confirmation of their screening CD4 count, to have another blood sample drawn and to return their questionnaire. Participants were paid $25.00 at that time. After completing all of these procedures, participants were randomly assigned to either the experimental (10-week CBSM intervention) or control condition.

After completion of the 10-week intervention or the 10-week wait-list period (control subjects), participants returned to the study office to complete another psychosocial questionnaire, have blood drawn, and undergo physical examination. Participants were again paid $25.00 for their participation at this time.

Intervention condition.
Subjects participating in the experimental condition attended a 10-week group-based CBSM intervention, referred to as the GET SMART (Group-Experienced Therapy for Stress Management and Relaxation Training) intervention. Each group typically consisted of 4 to 8 participants and met weekly for approximately 21/2 hours per week. Groups were led by advanced clinical health psychology predoctoral graduate students or postdoctoral fellows according to a training manual and received weekly face-to-face supervision by a licensed clinical psychologist and a board-certified psychiatrist. The intervention focused on a variety of cognitive-behavioral stress-reducing techniques, and each session consisted of a relaxation training exercise and didactic component. In the didactic component, group leaders presented various stress management techniques and participants were urged to discuss the techniques and relate them to the stressors in their lives as often as possible. In addition, each session included one or more activities designed to facilitate group discussion and increase the participants’ ability to comprehend and practice the relevant techniques. For example, sessions may have included in-session worksheets, role-playing exercises, or group interaction exercises. Topics focused on in the intervention included increasing awareness of stressors and the stress response, cognitive self-monitoring and restructuring, coping skills training, assertiveness training, anger management, and identification and enhancement of social support.

CBSM participants were also taught a variety of stress-reducing relaxation techniques during the course of the intervention, including progressive muscle relaxation, imagery, breathing exercises, autogenics, and meditation. Participants were encouraged to practice the techniques presented each week outside the group and were given structured homework exercises to facilitate practice. Weekly homework assignments typically consisted of one or more written self-monitoring assignments (eg, a cognitive restructuring monitoring sheet) and daily relaxation practice. As described previously, participants were given daily self-monitoring cards to monitor their adherence to out-of-session relaxation practice and to record their levels of stress both before and after practice.

Control condition.
Participants in the wait-list control condition completed pre- and postassessments identical to those completed by subjects in the intervention condition. After their 10-week follow-up assessment, control subjects were invited to attend a 1-day group stress management seminar. During this seminar, participants were taught several of the stress management and relaxation techniques that were taught during the 10-week CBSM intervention.

Statistical Analyses
Changes in psychosocial and physiological measures after the 10-week intervention period were assessed using separate univariate 2 x 2 (group assignment by time point) repeated-measures ANOVAs. Significant interaction effects were followed up by within-groups tests of simple effects. Relationships among changes in HSV-2 IgG, social support, hormone levels, and relaxation measures were assessed using Pearson’s correlation coefficients. Tests of mediation were conducted using linear regression as outlined by Baron and Kenney (50).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
Sample Characteristics
One hundred asymptomatic or early symptomatic HIV-infected homosexual or bisexual men with a CD4 count >=200 cells/mm3 and evidence of comorbid diseases or major psychopathology were recruited to participate in the study. Three subjects were excluded because of reported drug use just before their assessment or positive results on their urine toxicology screen. An additional two subjects were excluded because they had changed HIV medications either just before or just after entering the study. To reduce the heterogeneity of the sample’s immunologic status due to changes in HIV treatment regimens over time, only those subjects known to not be on protease inhibitor medications during the 10-week intervention were included, resulting in 16 exclusions. Of the remaining 79 subjects, 13 were excluded from the present analyses because they were HSV-2 seronegative, and an additional 4 were excluded because some of their baseline HSV-2 data were missing. The final sample consisted of the remaining 62 men who completed the 10-week intervention or wait-list control period and had at least baseline HSV-2 data.1

Comparison of these 62 subjects to the excluded subjects using independent samples t tests and {chi}2 statistics demonstrated no significant differences between groups in age, CD4 count, number of HIV symptoms, time since HIV diagnosis, education, ethnicity, employment status, income, living arrangement, and relationship status (all p values .05).

Participants were between the ages of 24 and 51 years, with a mean age of 36.70 years (SD = 7.1 years). The majority of subjects were either white (61%) or Hispanic (32%) and had at least some college education (85%). The average length of time since HIV diagnosis to study enrollment was 41/2 years (mean = 54.08 months, SD = 36.3), and the typical participant (50%) had experienced one to two HIV-related symptoms before study entry (mean = 1.95, SD = 1.8). Mean CD4 count at baseline was 441.64 cells/mm3 (SD = 231.1 cells/mm3). The majority of subjects worked at least part time (77%); considered themselves either Catholic (42%), Protestant (27%), or Jewish (13%); and lived either alone (47%) or with a lover (27%). Modal income was between $20,000 and $30,000. Finally, the majority of subjects were not involved in a steady relationship (57%) at the time of initial assessment, with another 39% involved in either an "open" or "closed" relationship.

Of the 62 participants in the present study, 41 were randomly assigned to the CBSM condition and 21 were assigned to the control condition.2

2 analyses revealed no significant differences between groups in baseline HIV medication status, CDC HIV disease stage, ethnicity, living arrangements, employment status, or education (p values > .05). Independent-samples t tests also revealed that the groups did not differ significantly in age or baseline CD4 count (p values > .05). Furthermore, analysis of baseline group differences in the outcome measures studied (ie, mood, cortisol/DHEA-S ratio, and HSV-2) showed that the CBSM and control groups were similar on all measures (all p values > .05)

Changes in HSV-2, Mood, and Cortisol/DHEA Ratio
Separate univariate 2 x 2 (group assignment by time point) repeated-measures ANOVAs revealed significant group-by-time interactions for HSV-2 IgG (F(1, 60) = 4.02, p < .05) and cortisol/DHEA-S ratio levels (F(1,41) = 5.39, p < .03). A significant group-by-time interaction effect was also found for POMS TMD (F(1,52) = 4.15, p < .05). Follow-up tests of simple effects demonstrated that there were significant reductions in HSV-2 IgG antibody titers (t40 = 2.24, p < .04) in the CBSM subjects and no changes among control subjects (p > .10). There was no change in cortisol/DHEA-S ratio levels in the CBSM group (p > .10), although control subjects showed a significant increase in this ratio over the 10-week period (t16 = -2.27, p < .04). There was also a significant reduction in POMS TMD (t35 = 2.57, p < .02) scores in the CBSM subjects with no similar changes occurring in the control group subjects (p > .10).

Associations Among HSV-2 Antibody Titers, Mood, and Cortisol/DHEA-S Ratio
Change scores were computed for the variables that demonstrated significant changes across the 10-week intervention or wait-list period. We considered the possibility that changes in HSV-2 IgG titers measured might simply be reflective of changes in nonspecific polyclonal B cell activation and thus controlled for changes in total IgG titer levels as well as baseline BMI, which may have implications for levels of DHEA-S (52). When changes in total IgG and baseline BMI were controlled for, the correlation between {Delta}HSV-2 IgG and {Delta}cortisol/DHEA-S ratio actually became significant (rp = 0.31, p < .05; see Figure 1 for scatterplot without covariates). Changes in HSV-2 IgG were not significantly correlated with POMS TMD changes (p > .10). Table 1 gives descriptive data for the major study variables associated with changes in HSV-2 IgG.



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  		Fig. 1. Bivariate distribution of pre- and posttreatment HSV-2 IgG antibody titer levels and cortisol/DHEA-S ratio ({Delta}) change scores.

 

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  		Table 1. Pre- and Postintervention Means and Standard Deviations for Major Study Variables
 
Do Social Support Changes Mediate the Effect of CBSM on HSV-2 IgG Reductions?
Because our prior work indicated that CBSM affects two indices of social support in particular, guidance and reliable alliance, in HIV+ men (24), we tested whether changes in these social support facets acted to mediate the effect of CBSM on HSV-2 titers in the present study. Separate repeated-measures ANOVAs revealed a significant group-by-time interaction effect for SPS guidance (F(1,53) = 4.22, p < .05) but a nonsignificant interaction effect for reliable alliance (F(1,53) = 2.98, p < .09). Specifically, significant increases in SPS guidance were observed in the CBSM group (t35 = -2.69, p < .01) during the intervention, but no significant changes over time were noted in the control group (see Table 1).

At the individual level, changes in HSV-2 IgG antibody titers were negatively correlated with changes in SPS guidance scores (r = -0.33, p < .01), indicating that as perceptions of guidance increased over the 10 weeks, HSV-2 IgG antibody titers decreased (see Figure 2). Controlling for changes in total IgG, the correlation between change in HSV-2 IgG and guidance remained significant (rp = -0.35, p < .01).



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  		Fig. 2. Bivariate distribution of pre- and posttreatment HSV-2 IgG antibody titer levels and SPS guidance ({Delta}) change scores.

 
Baron and Kenny’s (50) model of mediation was used to test social support as a mediator of CBSM effects on HSV-2 IgG levels. First, HSV-2 change was regressed on group assignment and then separately on SPS guidance change scores (after first controlling for change in total IgG). Second, SPS guidance change was regressed on group assignment. Because these analyses revealed significant ß ßeights (see Figure 3), a final analysis was conducted in which HSV-2 IgG change was first regressed on the potential mediator (SPS guidance) and then on group assignment. Mediation, or partial mediation, is said to occur if the ß weight of group assignment reduces, while the potential mediator retains, its significant ß weight in the final analysis (50). As shown in Figure 3, change in SPS guidance acted as a partial mediator of the effect of group assignment on HSV-2 IgG changes. Specifically, after controlling for the effect of changes in SPS guidance on changes in HSV-2 IgG, the ß weight of group assign-ment dropped from 0.25 to 0.11, indicating that group assignment no longer predicted changes in HSV-2 IgG.



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  		Fig. 3. Mediation analysis showing the relationship between group assignment and change in HSV-2 IgG antibody titers once changes in SPS guidance are controlled for. HSV-2 IgG values were first regressed on change in total IgG levels. Numbers inside parentheses represent standardized ß weights in the regression analysis. *p < .10; **p < .05; ***p < .01.

 
Contributions of Relaxation to CBSM Effects
Several relaxation "dose" variables were investigated as potential correlates of HSV-2 changes within the CBSM group.3

Specifically, amount of at-home relaxation practice, mean change in stress levels after at-home relaxation practice, and mean pre- and postrelaxation stress levels for at-home relaxation practice were examined. The only significant association observed was a negative correlation between change in HSV-2 IgG and mean postrelaxation stress levels (r = -0.35, p < .03; see Figure 4). This association remained significant after controlling for change in total IgG levels across the intervention period (rp = -0.35, p < .03). However, after also controlling for mean prerelaxation stress levels, the association between HSV-2 IgG change and mean postrelaxation stress levels became nonsignificant (rp = -0.31, p < .07). This relationship suggests that although total adherence to home practice of relaxation among CBSM subjects was not associated with immune changes, individuals who reported a lower level of stress after practicing relaxation at home tended to demonstrate greater decreases in HSV-2 antibody titers over time.



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  		Fig. 4. Bivariate distribution of {Delta} pre- and posttreatment HSV-2 IgG antibody titer levels and mean postrelaxation stress levels.

 
Analysis of Potential Confounding Variables
In addition to change in overall IgG during the course of the intervention, several other variables were also investigated as potential confounders of the HSV-2 effects observed. Correlations were computed between alcohol use, coffee consumption, cigarette use, hours of exercise and sleep, age, and CD4 counts on one hand and HSV-2 IgG on the other to determine which variables should be controlled for in the correlation analyses. However, no significant correlations were observed.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
We found that HIV+ men participating in a CBSM intervention had significant decreases in HSV-2 IgG titers over the 10-week intervention period, whereas men in the control condition demonstrated no changes. These reductions in HSV-2 antibody titers seen in CBSM participants suggest improved cellular control over this latent virus, a pattern we have observed previously (21, 53). Our results also showed that increases in one type of social support, perceived receipt of guidance, during the 10 weeks were associated with decreases in HSV-2 IgG and, in fact, partially mediated the effect of CBSM on HSV-2 IgG titers. Similarly, decreases in cortisol/DHEA-S ratio levels were associated with decreases in HSV-2 IgG, although this hormonal ratio did not act as a mediator of the intervention’s effect. Finally, lower mean stress levels reported after (but not before) at-home relaxation practice were also associated with greater decreases in HSV-2 IgG among CBSM participants.

Distress, Relaxation, and HSV
Changes in anxious mood or overall mood disturbance were not related to HSV-2 IgG changes across the 10-week intervention period. Although several studies have demonstrated such an association between mood and HSV antibody titers (15, 17, 19, 54), others have not (27, 55). Because our assessment of anxiety was at single points in time before and after a period of 10 weeks, it may not have been sensitive enough to capture peaks in mood disturbance (on a daily basis or surrounding a major life event), which might be better predictors of viral reactivation. Within the CBSM condition it was participants’ ability to achieve a low level of stress through daily relaxation practice, not just their average prerelaxation stress level, that was predictive of HSV-2 IgG reductions. Our previous work has shown that regularity of relaxation practice was related to changes in immune status (56). The present study expands on these findings to suggest that it may actually be the efficacy in using relaxation strategies to reduce stress that may have significant immunologic implications. Men who were able to effectively reduce bodily tension and perceived stress in their daily lives, outside the CBSM sessions, achieved the greatest reductions in HSV-2 antibody titers.

Social Support and HSV
We found that the maintenance and improvement in social support over the 10-week period partially explained intervention-associated HSV-2 IgG reductions. The influence of social support and social relationships on psychological distress (24) and health and immune status (57–59) has been documented in HIV-infected persons as well as healthy individuals (60, 61); this is the first study to demonstrate this association in the context of an intervention. Some work suggests that the health impact of social support may come about through improved psychological well-being or adoption of more healthy behaviors and improved relationships with critical healthcare providers (23). Prior research has explored the mechanisms involved in stress-related reactivation of HSV (62–65), particularly those involving social stressors (66). Future work should explore the mechanisms through which intervention-related change in social support may protect against HSV reactivation by exploring its effects on behavioral as well as neuroendocrine pathways.

Adrenal Hormones and HSV
We found that reductions in plasma cortisol/DHEA-S ratio levels were associated with HSV-2 IgG decreases during the intervention period. Glucocorticoids have an immunosuppressive effect, presumably a mechanism designed to protect from overactivation of the immune system (34, 67). Adrenocortical pathways have been implicated in stress-associated suppression of immune responses to HSV (64). Conversely, immunoprotective aspects of DHEA and DHEA-S have been documented (68, 69). One aspect of the impact of DHEA on immune functioning seems to be its antiglucocorticoid effects (70); that is, it acts in a homeostatic relationship with cortisol and may protect against the immunosuppressive effects of glucocorticoids. Androstenediol, a metabolic product of DHEA, enhances the survival of mice infected with HSV-1, potentially by enhancement of TH1 cytokines, particularly interferon-{alpha} and, in turn, natural killer cell cytotoxicity and HSV-specific cytotoxic T-cell activation (71, 72).

Although we found several independent predictors of HSV-2 antibody titer changes, it is significant to note that only social support changes mediated the effect of the CBSM intervention and that the three predictors, cortisol/DHEA-S ratio levels, guidance, and relaxation efficacy, were not interrelated in this sample (p values > .10). This suggests that these components of CBSM were acting somewhat independently to influence HSV-specific elevations. Additional research is needed to more clearly elucidate the mechanisms through which social support and cortisol and DHEA-S levels affect HSV-2 reactivation.

This study was conducted with a group of presumably highly motivated HIV-infected gay men, and thus the findings may not generalize to other populations, including women, heterosexual men, individuals infected through other routes (eg, intravenous drug use), and those who are less educated or less motivated. Future work should investigate the effects of this intervention on recurrence of clinical symptoms of HSV-2 as well as changes in immune function, given recent work suggesting that stress may trigger HSV-2 outbreaks over time in healthy persons (27). The present findings suggest that group-based interventions that teach stress-reducing techniques such as relaxation, enhance social support, and influence adrenal pathways may have important implications for the psychological and physical well-being of HIV-infected persons.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
REFERENCES
 
This work was funded by the National Institutes of Health (Grants P01 MH49548 and T32 MH18917).


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
ACKNOWLEDGMENTS
 REFERENCES
 
1Some men did not have follow-up HSV-2 IgG (eight subjects), cortisol/DHEA-S ratio (nine subjects), or total IgG (seven subjects) data because they missed an assessment or no blood was drawn at the time of assessment. Conservative linear regression techniques (51) were used to substitute these missing values using the largest sample available for each variable within the initial 100 subjects recruited. This method did not influence the results of the study because identical analyses using nonsubstituted data revealed the same pattern of results. Back

2 Subjects were randomly assigned to the CBSM or control group in a 2:1 ratio to facilitate within–CBSM group analyses. Back

3 Relaxation practice data were collected only from men in the CBSM group as part of their homework assignments. Back

Received for publication November 30, 1999.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 

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