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Psychosomatic Medicine 65:627-635 (2003)
© 2003 American Psychosomatic Society

ORIGINAL ARTICLES

Psychological Distress is Associated With Decreased Memory Helper T-cell and B-cell Counts in Pre-AIDS HIV Seropositive Men and Women but Only in Those With Low Viral Load

Sarosh J. Motivala, PhD, Barry E. Hurwitz, PhD, Maria M. Llabre, PhD, Nancy G. Klimas, MD, Mary Ann Fletcher, PhD, Michael H. Antoni, PhD, William G. LeBlanc, PhD and Neil Schneiderman, PhD

From the Behavioral Medicine Research Center (B.E.H.) and Department of Medicine (N.G.K., M.A.F.), University of Miami, Miami, Florida; the Department of Psychology (B.E.H., M.M.L., M.H.A., W.G.L., N.S.), University of Miami, Coral Gables, Florida; and the Cousins Center for Psychoneuroimmunology (S.J.M.), University of California, Los Angeles, California.

Address reprint requests to: Barry E. Hurwitz, PhD, Behavioral Medicine Research Center (200 BMRC), University of Miami, c/o VA Medical Center, 1201 NW 16th Street, Miami, FL 33125. Email: BHurwitz{at}miami.edu

Received for publication February 7, 2002; revision received September 11, 2002.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
OBJECTIVE: Although some studies have demonstrated the association of psychological distress and diminished immune system function in HIV spectrum disease, other studies have yielded apparently conflicting findings; the lack of consideration of the role of HIV viral burden may be central to this controversy. This study examined whether HIV viral burden moderated the relationship between psychological distress and enumerative and functional immune measures in pre-AIDS HIV spectrum disease.

METHODS: This cross-sectional study used factor analysis to derive a composite measure of psychological distress incorporating measures of dysphoria, anxiety, and perceived stress. Multiple regression analyses used distress as the predictor, immune measures as the outcome variables, with viral load as the moderator variable, while controlling for age, medication use, and HIV symptomatology. Subjects were 148 pre-AIDS, HIV seropositive men and women (89 asymptomatic, 59 symptomatic), aged 18 to 45 years. The main outcome measures were enumerative and functional immune measures.

RESULTS: A model of psychological distress was derived using each of the proposed measures. Findings indicated that high distress was associated with decreased numbers of helper T (memory) cells and B cells, but only at low levels of viral burden after controlling for age, medication use, and HIV-related symptoms.

CONCLUSIONS: These findings highlight the importance of assessing the role of HIV viral burden when examining distress-immunity relationships in HIV-infected individuals. The lack of association in those persons with high viral load suggests that, even before AIDS onset, disease-related processes are disrupting CNS and immune system communication.

Key Words: HIV-1, • psychological stress, • immune system, • viral load, • T lymphocytes, • B lymphocytes.

Abbreviations: AIDS = acquired immunodeficiency syndrome;; BDI = Beck Depression Inventory;; CDC = Centers for Disease Control and Prevention;; cDNA = clonal deoxyribonucleic acid;; EBV = Epstein-Barr virus;; ELISA = enzyme-linked immunosorbent assay;; CD3+CD4+ = helper T4 cells;; CD4+CD45RA-CD29+ = helper T4 cell memory cells;; CD4+CD45RA+CD29+ = transition helper T4 cells between the naive and memory state;; CD4+CD45RA+CD29- = helper T4 naive cells;; CD3+CD8+CD56- = cytotoxic/suppressor T8 cells that are not natural killer cells;; CD8+CD38+HLA/DR+ = cytotoxic-activated T8 cells;; CD8+CD38-HLA/DR+ = noncytotoxic-activated T8 cells;; CD19+ = B cells;; CNS = central nervous system;; C/S = cytotoxic/suppressor cells;; HIV-1 = human immunodeficiency virus type 1;; IES = Impact of Events Scale;; NK or CD3-CD8-CD56+ = natural killer cell that is not a cytotoxic/suppressor T8 cell;; NKCC = natural killer cell cytotoxicity;; PHA = lymphoproliferative response to the plant mitogen, phytohemagglutinin;; POMS = Profile of Mood States;; PSS = Perceived Stress Scale;; RNA = ribonucleic acid;; SCID = structured clinical interview for DSM-III-R.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
It is well established that acute and chronic psychological distress are associated with immunosuppression and enhanced risk for infectious illness in healthy populations (1–4). In studies examining the predictive impact of distress on the pathophysiology of human immunodeficiency virus type 1 (HIV-1) infection, the results have been less consistent. These studies primarily used depressive symptomatology as the immune status predictor. A recent report showed that depressive symptoms at baseline were predictive of mortality and decreases in helper T cells in a sample of 765 HIV seropositive women (5). Another longitudinal study of 330 HIV-infected men found evidence 5 years poststudy entry that depressive symptoms predicted decreases in helper T-cell numbers (6) and showed that depression predicted disease progression and increased mortality risk at a 9-year follow-up (7, 8).

In contrast, other studies have failed to show that psychosocial factors predict a decline in helper T cells and other immunological parameters (9–11). For example, a large prospective study of 1357 HIV-infected men without AIDS reported that depressive symptoms did not predict immune status, HIV disease progression, or mortality 8 years later (11). In addition, in a sample of 66 HIV-infected men, elevated stressful life events and depressive symptoms were not predictive of disease progression 2 years later, as indicated by helper T-cell counts, but were associated with decreased numbers of cytotoxic/suppressor (C/S) T cells and natural killer (NK) cells (12). This latter study is noteworthy because it did not measure depressive symptoms alone but also assessed stressful life events.

One possible reason for the conflicting findings in the distress-immune status literature may be that HIV viral burden, as indexed by viral load, has not been adequately controlled. It has been clearly shown that viral load predicts mortality better than helper T counts and HIV symptom classification and hence may be a superior reflection of disease severity (13). However, probably due to the more recent advent of technology to measure viral load, viral burden has not been used in this literature. The need to control HIV viral burden is supported by the fact that the HIV-infected participants in some of the studies that reported negative findings were at a more advanced stage of helper T cell loss (9, 11). Thus, in more-disease-progressed individuals, the degree of immune impairment may be profound enough to obscure any psychosomatic relationship between distress and immune parameters.

Another possible reason for these apparently contradictory findings may have to do with the restricted use of depressive symptomatology as the predictor of immune status. The distress associated with the psychosocial pressures of HIV infection can be manifested in ways other than dysphoria and depressive symptomatology, including heightened anxiety, worries, tension, perceived stress, and avoidant, intrusive, and overwhelming thoughts (14–17). For example, measures of anxiety were predictive of declines in CD4/CD8 ratio at 1-year follow-up, in a sample of 67 HIV-infected women (18). In a sample of 82 HIV seropositive men who were pre-AIDS at baseline, stressful life events, lower satisfaction with social support, and denial as a coping strategy were found to predict faster progression to AIDS over a 7 to 8 year period, independent of baseline T helper cells, medication use, and HIV-1 viral load (19, 20). Moreover, in a previous cohort, these researchers found that higher severe life stress increased the risk of HIV disease progression four-fold (21). Similar associations of psychological and immune factors have also been reported in other longitudinal (22) and cross-sectional studies of HIV-infected individuals (14, 23). Thus, the present study incorporated into a single construct measures of dysphoria, anxiety, and perceived stress, which were broadly conceived as measures of psychological distress, and assessed its association with immune status.

Therefore, to determine whether there are differences in the strength of the distress-immune relation at varying levels of disease severity, the primary objective of the present study was to evaluate whether HIV-1 viral load moderated the association between psychological distress and enumerative and functional measures of immune status in HIV-1 infected men and women. Because the memory subset within the helper T-cell pool undergoes a more rapid decline with HIV progression than the naive subset (24, 25), one secondary objective was to determine whether memory, naive to memory transition, or naive helper T-cell subsets differentially account for the strength of the distress-helper T-cell relationship. In addition, because evidence indicates the activated cytotoxic/suppressor (C/S) T cell that is negative for the phenotypic expression of the CD38 marker may be protective in long-term HIV survivors (26), another secondary objective was to assess whether cytotoxic and noncytotoxic activated C/S T-cell subsets were differentially associated with distress.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects
The 148 HIV-1 seropositive individuals (89 HIV asymptomatic clinical category A and 59 HIV symptomatic clinical category B, based on the revised CDC classification system (27)) who met study entry criteria (see below) were recruited from the surrounding Miami-Dade and Broward communities. Participants were part of a larger study assessing acute mental stress-induced cardiovascular, autonomic, and immunocellular function in HIV spectrum disease (28).

Subjects were excluded if they presented with clinical symptoms of AIDS or if their helper T-cell (CD3+CD4+) counts were < 200 cells/mm3. Alcohol and drug abuse and previous psychiatric history were assessed by questions from the Structured Clinical Interview (29) for the DSM-III-R, adapted for use with nonpatient HIV subjects (SCID-NP-HIV). Individuals reporting intravenous drug use within 6 months before study entry, a history of heavy cigarette smoking (>50 pack/year), or who arrived at the laboratory under the influence of illicit drugs or alcohol as assessed by self-report, SCID interview, or urine toxicology testing were excluded. Cognitively impaired subjects as assessed by a Mini-Mental Status Exam (score <= 26) were also excluded (30).

Subjects with concurrent clinical levels of depression (moderate or greater) defined as a score > 15 on the Hamilton Rating Scale for Depression (31) and individuals who had been bereaved of a significant other within the past 3 months were excluded from study participation. In addition, subjects were excluded for current psychiatric or neuropsychological conditions, concurrent engagement in psychotherapy, and use of psychoactive drugs. Those recently bereaved, depressed, or with psychiatric conditions or those who were receiving concurrent psychotherapy or psychoactive medications were excluded because the objective of the study was to examine the distress associated with HIV infection as opposed to distress influenced by other conditions or their interventions.1

Other exclusion criteria were hypertension (blood pressure > 140/90 mm Hg); use of antihypertensive or cardiovascular-related medication; current use of hormones such as oral contraceptives; postmenopausal status or hysterectomy; use of immunomodulatory medications such as systemic corticosteroids and antihistamines within the previous 3 months; recent surgery requiring anesthesia or hospitalization; recent pregnancy within 3 months of study entry; and history of cardiovascular, diabetic, or other major systemic disorder.

This community-based study was diversely represented by ethnicity, gender, and sexual orientation. Forty (27%) subjects were non-Hispanic white, 39 (27%) were Hispanic, and 69 (46%) were African-American. Ninety-seven (66%) subjects were men and 51 (34%) were women, representing heterosexual (48%), homosexual (35%), and bisexual (9%) orientations. The subjects were aged 18 to 45 years (mean ± SD: 33.2 ± 6 years) and had a modal income range of $5,000 to $10,000. Most subjects (53%) had graduated high school or had some high school or trade school education, and the remaining (47%) had some college or graduate education. These present data were collected from 1993 to 1998 and hence were largely collected before the advent of protease inhibitor therapy (3% protease inhibitor use in this study). The majority (65%) of subjects (74% asymptomatic, 51% symptomatic) were not being treated with HIV medication; 20% (15% asymptomatic, 29% symptomatic) were treated with monotherapy; and 15% (11% asymptomatic, 20% symptomatic) were treated with combination therapy.

Procedure
Subjects underwent a screening session in which the following were obtained: 1) informed consent; 2) HIV antibody status using both ELISA and Western blot methods; 3) HIV diagnosis date; 4) physical exam; 5) urine toxicology; 6) HIV-related symptoms history; and 7) medications and drug-use history. Subjects also completed psychosocial questionnaires, a SCID interview, and a Mini-Mental Status exam. Within about 2 weeks, the mental stress testing session was held (for protocol details see 28). After an overnight stay in the General Clinical Research Center, subjects consumed a light breakfast (no caffeine) and were escorted to the Behavioral Medicine Research Center about 8 AM. At 24.5 and 27 minutes of a seated rest period, intravenous blood was collected for immune assay from which mean values were derived. Subjects were compensated for their participation on study completion.

Predictor Variables: Psychosocial Measures
From the Profile of Mood States (POMS) survey, 65 feelings (eg, confused, listless, gloomy, tense) were rated on a scale of 1 to 5 as to how frequently in the past week they were experienced (40). The POMS depression and anxiety sub-scales were assessed. These two subscales have measures of internal consistency that are above 0.90 and test-retest reliability above 0.70 (40). The Beck Depression Inventory (BDI), a 21-item survey, assessed the behavioral, vegetative, cognitive, and affective signs of depression (41). The internal consistency has been shown to be above 0.86 and test-retest reliability above 0.59 (41). Because the BDI has items that could be confounded with the somatic symptoms of HIV, as has been done with other medical populations, the BDI items were divided into two components: dysphoria symptoms, items 1 to 13, and somatic symptoms, items 14 to 21 (42, 43). The Impact of Events Scale (IES), a 15-item survey, includes two subscales: assessed thought intrusions and avoidances associated with distress about life situations regarding the subjects’ HIV infection (44). Internal consistency and test-retest reliability for the intrusions subscale is above 0.77 and 0.88, respectively, and for the avoidance subscale is above 0.81 and 0.78, respectively (44). The Perceived Stress Scale (PSS), a 14-item survey, measured the degree to which individuals appraised their life within the past month as stressful on a scale from 0 ("never") to 4 ("very often") (45). This measure has an internal consistency above 0.84 and short-term test-retest reliability above 0.84 (45).

Outcome Variables: Enumerative and Functional Immune Measures
Enumerative measures were determined using two- and three-color direct immunofluorescence techniques described previously (46). In addition to total helper T-cell (CD3+CD4+) counts, three subsets were derived: memory cells (CD4+CD45RA-CD29+), transition cells between the naive and memory state (CD4+CD45RA+CD29+), and naive cells (CD4+CD45RA+CD29-). In addition to total C/S T-cell counts (CD3+CD8+CD56-), two subsets were measured: cytotoxic-activated cells (CD8+CD38+HLA/DR+) and noncytotoxic-activated cells (CD8+CD38-HLA/DR+). Total B-cell (CD19+) and natural killer (NK)-cell (CD3-CD8-CD56+) counts were also determined.

Functional measures included natural killer cell cytotoxicity (NKCC) and the lymphoproliferative response to the plant mitogen, phytohemagglutinin (PHA). The NKCC against the erythroleukemic K562 cell target was measured in triplicate at four effector-to-target ratios, using a whole blood chromium release assay as previously detailed (47). The NKCC was derived for CD56+CD3-cells only. Percent cytotoxicity was expressed at an effector-to-target ratio of 1:1. The lymphocyte proliferation response to PHA at 10 µg/ml was tested in triplicate using a whole blood method previously outlined (47). The mean of the three net cpm was derived and converted to cpm/100,000 cells and then normalized.

Moderator Variable: Viral Burden
Plasma HIV RNA was measured using an in vitro nucleic acid amplification test (Amplicor HIV-1 Monitor Test). The test involves: 1) reverse transcription of target RNA to produce cDNA; 2) polymerase chain reaction amplification of target cDNA; 3) hybridization of amplified product to oligonucleotide probes; and 4) detection of probe-bound product by colorimetric determination. Viral load was quantified in number of HIV RNA copies/ml and normalized by log transformation.

Control Variables: Age, Medication Usage, and HIV Symptoms
Age was used as a control variable. By their self-report and confirmed later during the physical exam, subjects were asked to detail their prescribed and nonprescribed medication usage. Anti-HIV medications were quantified as follows: 0 = no medication therapy; 1 = monotherapy; 2 = combination therapy. The occurrence of HIV-related symptoms in the 6 months before study entry was also documented. These symptoms included CDC category B symptoms (27), as well as the following noncategory defining symptoms: lymphadenopathy, splenomegaly, hepatomegaly, night sweats, and weight loss greater than 15 lb or 10% over a 3-month period. The number of reported symptoms was summed to yield a total symptom index.

Statistical Analyses
This study employed a cross-sectional design in which the statistical analyses comprised two main objectives. The first objective was to use factor analytic methods to derive a model of psychological distress using the psychosocial measures described above, then generate "distress" factor scores. The second objective was to conduct a series of multiple regression analyses to assess whether distress (ie, distress factor scores) was associated with immune status (ie, enumerative and functional immune measures) when viral burden (ie, viral load) was used as a moderator variable, while controlling for age, medication use, and HIV-related symptoms.

Modeling Psychological Distress
The psychosocial measures used were: 1) BDI, including only the items reflecting dysphoric symptoms2 (ie, items 1–14); 2) POMS, depression and anxiety scales; 3) IES, thought intrusion and avoidant thought subscales; 4) PSS, total score. A varimax unrotated factor analysis (PROC FACTOR, SAS Institute Inc., Cary, NC) was conducted to determine if these measures comprised one factor or instead reflected different but correlated underlying constructs. The scores for each questionnaire were transformed into Z scores, which were then used in the regression equation to derive the distress factor score.

Testing Viral Burden as a Moderator of the Distress-immune Relation
A series of moderator regression analyses were undertaken in which the nine immune measures were used separately as outcome variables. A variable is defined as a moderator when different levels of that variable are associated with different relationships between the predictor and an outcome variable (48). For example, if the relationship between distress and the immune measure were present for persons with low viral load but not present for those with high viral load, viral load would then be said to moderate the distress-immune relation. Because recent evidence indicates that the acute impact of HIV infection results in highly variable helper and C/S T-cell counts that do not stabilize until after approximately 1 year of infection (49, 50), only subjects whose time since HIV diagnosis was greater than 1 year were used in these regression analyses; thus, 23 subjects were excluded. Viral load and distress were centered (means set to 0) to reduce multicollinearity. The control variables (age, medication use, and HIV-related symptoms), distress index, viral load, and their interaction were then included in the regression model. The finding of a significant interaction between the proposed moderator and the predictor variable indicates a moderator effect (48).

For follow-up tests of significant interactions, a method described by Aiken and West (51) was used. This method involves following up significant interactions in multiple regression analysis with testing that maintains statistical power by incorporating all sample variance without segregating or removing data, such as when median splits are used.3 Follow-up tests of significant interactions were assessed by generating two values of viral load to designate "high" and "low" viral load levels, 1 SD above and 1 SD below the mean, respectively, and generating two regression equations, one for each viral load value. Then, two values of distress (high vs. low), 1 SD above and 1 SD below the mean, respectively, were entered into the each of these regression equations. Thus one regression equation for high viral load and one equation for low viral load were derived. Then each coefficient for the distress factor was tested, wherein a value significantly different from zero indicates that the predictor, distress, was associated with the outcome immune measure.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
Immune Status, Disease Severity, Time Since Diagnosis, and HIV-Related Symptoms
Of the 148 subjects who met entry criteria, 16 evidenced poor or insufficient blood samples, leaving 132 subjects for whom enumerative immune measures were obtained (Table 1). Viral load data were not obtained for one additional subject due to procedural error. For the functional immune measures, the PHA response was not obtained for an additional five subjects and NKCC was not obtained for an additional four subjects due to technical difficulties. For descriptive purposes, the measures of HIV and immune status are depicted in Table 1 as a function of HIV symptom classification. The HIV symptomatic individuals had significantly fewer helper T cells than asymptomatic subjects [F(1,130) = 8.9, p < .005]. This difference was reflected in the memory helper T-cell subset [F(1, 130) = 4.8, p < .05] and the transition helper T-cell subset [F(1, 130) = 8.6, p < .005] but not in the naive helper T-cell subset. In addition, symptomatic subjects had greater numbers of C/S T cells than asymptomatic subjects [F(1,130) = 7.5, p < .01]. The groups did not differ for any other enumerative or functional immune measure nor did they differ in viral load or time since diagnosis; however, as expected, HIV symptomatic subjects reported a significantly greater number of HIV-related symptoms than asymptomatic subjects [F(1, 146) = 116.6, p < .0001].


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  		TABLE 1. Basal Enumerative and Functional Measures of Immune Status as a Function of HIV Symptom Classification
 
Psychological Distress
Three subjects did not complete the IES, two did not complete the POMS anxiety scale, four did not complete the POMS depression scale, and one did not complete the PSS, leaving 138 subjects contributing to the factor analytic modeling of distress. The proposed psychosocial measures met the basic assumptions required for generating factor scores (see Table 2 for mean ± SD, skewness, and kurtosis values) (51). The varimax unrotated factor analysis confirmed that the proposed psychosocial measures loaded on a single factor ({lambda} = 3.12), conceptualized as psychological distress. The scree plot was consistent with a one-factor model; the eigenvalue for factor 1 was 3.125, and the value for factor 2 was 0.482. As shown in Table 2, the factor loadings were moderate to high. Each transformed score was used in the distress factor score equation (see Table 2 for this equation), where they were weighted based on the factor analysis results. Psychosocial measures highly correlated (p values < .0001) with the distress factor score as follows: BDI dysphoria (r = 0.73); POMS depression (r = 0.86); POMS anxiety (r = 0.79); IES thought intrusion (r = 0.79); IES avoidant thought (r = 0.67); and PSS (r = 0.75). The distress factor was weakly correlated with number of HIV-related symptoms (r = 0.19, p < .05). However, the distress factor score was not significantly correlated with HIV viral load or any other immunological measure.


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  		TABLE 2. Descriptive Information for the Psychological Distress Model and Composite Measures
 
The observed scores on most of the psychosocial measures contributing to the distress factor were elevated compared with previous reports of healthy individuals (43–45). Notably, both avoidant and intrusive thought IES scores, which were developed to measure the impact of unpleasant, traumatic events, were substantially elevated. These scores were comparable with the scores previously observed in persons coping with a natural disaster (52) and more than double the scores of medical students (44).

Testing Viral Burden as a Moderator of the Distress-Immune Relation
Multiple regression analyses revealed a significant interaction between viral load and distress for helper T-cell counts [F(1,91) = 4.15, p < .05]. The covariates (age, symptoms, and medication use), distress, and viral load explained 34% of the variance; the interaction term added another 4%. The regression analysis showed that medication use was a significant covariate, [F(2,91) = 9.28, p < .001] but neither age nor HIV symptom count were significant. There was no significant main effect for distress with helper T-cell counts or any other immunological variables. In contrast, and as expected, there was a significant main effect for viral load [F(1,91) = 30.54, p < .0001], such that higher viral load was associated with lower helper T-cell counts. Follow-up tests were aimed at answering the question: Is distress related to helper T-cell count at a fixed level of viral load? Thus, when viral load was fixed at 1 SD above the mean, there was no significant relationship between helper T-cell counts and distress. However, when viral load was fixed at 1 SD below the mean, distress was inversely related to helper T-cell counts [F(1,91) = 4.15, p < .05]. To confirm the consistency of these findings, the relationships were tested at 1.5 and 2 SDs above and below the mean for viral load. The same pattern of findings emerged at these values of viral load for helper T-cell and memory helper T-cell and B-cell counts. For illustrative purposes, Figure 1 displays the relationships between helper T cells, distress, and at high and low HIV viral load.



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  		Fig. 1. Interaction between distress and viral load for helper T-cell count. Low and high plots represent values 1 standard deviation above or below the mean for both viral load and the distress index. The standardized coefficient for distress at low viral load was ß = -0.28, p < .05.

 
Examination of whether the viral load moderational effect was differentially present in the three helper T-cell subsets revealed a significant viral load and distress interaction only for the analysis of the memory helper T-cell subset [F(1,91) = 4.68, p < .05]. The covariates (age, symptoms, and medication use), distress, and viral load explained 31% of the variance; the interaction term added another 3%. As above, medication use was a significant covariate [F(2,91) = 6.39, p < .01]. Age was also a significant covariate [F(1,91) = 5.85, p < .05] but symptom count was not. There was a significant main effect for viral load [F(1,91) = 24.55, p < .0001], such that higher viral load was associated with lower memory helper T-cell counts. Follow-up tests indicated that when viral load was fixed at 1 SD below the mean, distress was inversely related to memory helper T-cell counts [F(1,91) = 3.79, p < .05]. However, distress was not significantly related to memory helper T-cells when viral load was high (ie, 1 SD above mean). The simple regression plots are shown in Figure 2.



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  		Fig. 2. Interaction between the distress and viral load for the memory helper T-cell subset count. Low and high plots represent values 1 standard deviation above or below the mean for both viral load and the distress index. The standardized coefficient for distress at low viral load was ß = -0.26, p < .05.

 
There was no significant main effect for distress nor were there any other significant interactions of distress and viral load with C/S T-cell and subset counts, NK cell count, nor with either of the functional immune measures, PHA blastogenesis and NKCC. However, a significant interaction was observed for B-cell count [F(1,91) = 4.01, p < .05]. The covariates (age, symptoms, and medication use), distress, and viral load explained 6% of the variance; the interaction term added another 3%. Neither medication use nor symptom count were significant covariates; however, age was a significant covariate [F(1,91) = 5.69, p < .05]. Follow-up analyses indicated a similar pattern of findings as indicated above; at low levels of viral load (1 SD below mean), distress was inversely related to B cells [F(1,91) = 3.64, p = .06] (2). In contrast, no relation between distress and B-cell count was found in subjects with high viral load (at 1 and 1.5 SD above mean). Figure 3 illustrates the simple regression plots for this interaction.



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  		Fig. 3. Interaction between distress and viral load for B-cell count. Low and high plots represent values 1 standard deviation above or below the mean for both viral load and the distress index. The standardized coefficient for distress at low viral load approached significance (ß = -0.30, p = .06) but was significant at 1.5 standard deviations (ß = -0.42, p < .05).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
Some HIV-infected persons develop symptoms rapidly and others remain free of AIDS symptoms for 10 to 15 years or more even in the absence of combination therapy (53). The influences responsible for the variability in HIV disease progression remain unknown but may be due to an interaction of biological and psychological factors (20, 54). The possibility that psychological distress may account for some of the variance in HIV disease progression was supported by the present findings. When employing the derived index of psychological distress, the present study confirmed that HIV viral burden, as indexed by viral load, does moderate the distress-immune association. Specifically, the major findings were that elevated distress was predictively associated with decreased helper T- and B-cell counts but only in HIV-infected individuals with low viral load. Furthermore, the relation with helper T cells was solely accounted for by the memory subset of helper T cells and not by the transition and naive lymphocyte subsets. Memory helper T cells perform a myriad of functions, primarily related to generating secondary responses to intracellular pathogens, producing cytokines, and regulating effector cell activity and proliferation (55); HIV preferentially attacks these cells (24).

This study is the first to use viral load to assess its moderational influence on the association of distress with immunocellular enumeration and function. Previous studies, although using differing disease severity measures, do provide support for the present findings of the moderational effect of viral load. The Burack study (6), in which a positive distress-immune association was observed, evidenced helper T-cell counts that were 20% greater than counts reported in the Lyketsos study (11) and 50% greater than counts from the Perry study (9), in which negative findings were reported. In addition, it was reported that when the Burack study (6) was reanalyzed, wherein only subjects having baseline helper T-cell counts below the median were included, there was no relationship between depression scores and helper T-cell counts; in contrast, for analyses using subjects above the median count, the relationship remained significant (56). Thus, previous negative findings were probably a consequence of these studies including subjects with more advanced disease severity. Psychological intervention studies provide further support for this suggestion, in which intervention-induced decreased distress is associated with more substantive immuno-enhancement in HIV asymptomatic subjects than in HIV symptomatic subjects (14, 57–61).

The possible mechanisms mediating the distress impact on immune status have been extensively documented (62). Briefly, chronic distress is posited to activate the hypothalamic-pituitary-adrenal cortex and sympathetic-adrenal medullary systems, resulting in the release of cortisol and catecholamines (63). These substances have been shown to induce an immunosuppressive effect via direct and indirect neural mechanisms influencing adrenergic and glucocorticoid receptors on lymphocytes and lymphoid tissue (64, 65). The stress-induced activation of the peptidergic arm of the autonomic nervous system may also lead to local release of neuropeptides, altering interactions with lymphocytes (66). A recent study found that, relative to a control group, HIV seropositive men, who were treated with a cognitive behavioral stress management intervention, displayed decreased urinary norepinephrine that was mediated by decreased anxiety and a smaller decrease in the rate of decline of C/S T-cell counts, which was mediated by the initial norepinephrine decrease (67). Therefore, not only do increases in distress seem to have negative immune effects but decreases in distress also seem to have consequences that are immunosupportive.

In addition to the potential immune effect of autonomic and neuroendocrine mechanisms, there is growing evidence that latent viral reactivation may facilitate the HIV infection of B cells (65). Herpesviruses, such as Epstein-Barr virus (EBV), which are normally under tight control in HIV seronegative individuals, become reactivated with HIV infection (68). The EBV acts as a cofactor enabling the B cell to be directly attacked by the HIV virion through expression of the CD4 receptor on coinfected B cells (60). In healthy individuals, stressful life events have been shown to induce herpesvirus reactivation (69) and depressive symptoms and increased perceived stress are associated with decreased B-cell numbers (2, 3). Although B-cell counts do not generally decline in pre-AIDS HIV disease (25), it is possible that heightened psychological distress can enhance the likelihood of latent virus reactivation, rendering infected B cells susceptible to HIV coinfection. Given that the HIV virus preferentially attacks helper T cells and B cells, the present findings are strengthened by the fact that it is these cells that seem to be uniquely sensitive to the moderation of the distress-immune association by viral load.

It is unclear why the distress-immune relationship was only present in those with low viral burden. One plausible explanation is that, with more advanced HIV disease severity, local deterioration of neural communication with lymphoid tissues and immune organs, as seen in progressive lymphadenopathy (25), may disrupt CNS communication with immune processes. Other more molecular immunocellular processes may contribute to this disruption, such as alterations in receptor trafficking or postreceptor mechanisms, which are progressively affected by HIV disease pathophysiology as well (70, 71). Nevertheless, given that an AIDS classification was exclusionary in the present study, the lack of association in those infected persons with high viral burden suggests that, before AIDS onset, disease-related processes may disrupt CNS and immune system communication.

The present distress-immune association findings were observed while controlling for anti-HIV medication therapy, the number of HIV-related symptoms, and age, indicating that psychological influences have an impact on immune processes over and above these factors. Some caution should be exerted when generalizing these findings to the present because these data were largely collected before the advent of protease inhibitors. However, combination antiretroviral therapy using protease inhibitors has been highly successful in reducing HIV viral burden, even to negligible levels when patients adhere to the medical regimen (72). Because the present findings show that the strength of the distress-immune relationship is greater in persons with low viral load, it is possible that, if this study had enrolled persons treated with current medication regimens, similar findings would be observed. Therefore, in current clinical practice in which improved control over viral replication occurs, factors that may combat the anti-HIV therapy effectiveness, such as psychological dysregulation, become an even more important consideration in the patient’s treatment plan.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
REFERENCES
 
This research was supported by National Institute of Mental Health (of the National Institutes of Health) research Grant MH49548. In addition, we gratefully recognize the technical contributions of the following people to this study: Kimberly Brownley, PhD; Alejandro Cazzaniga, BA; Lise Fillion, PhD; Julie Graves, MS; Jessie Hatfield, BA; Jackie Junco, MD; Karen Langman-Kuskin, RN; Pat Majors, MD; Jennifer Marks, MD; John Milanovich, PhD; and Maggie Olsen-Istel, BS.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
ACKNOWLEDGMENTS
 REFERENCES
 
1Bereavement and depression has been strongly associated with chronic stress and may have immune effects independent of those engendered by distress due to HIV infection (32, 33). Psychotherapy presents a complicated set of factors that may have various effects on distress and immune function (34–36). Similarly, both psychiatric conditions and psychoactive medications may have immunomodulatory effects or be CNS signs of more advanced HIV disease progression (37–39). The study design provides a conservative approach in which excluding based on these factors truncates variance and diminishes the possibility for finding significance. However, the advantage of this design is that potentially confounding factors were removed, which improved the sample homogeneity and provided some assurance that possible relationships would not be driven by a small number of extreme scores. Back

2The somatic items were excluded to obtain an index of dysphoria free of the confounding influence of physical symptoms that are associated with both depression and HIV (eg, fatigue, difficulty sleeping, weight loss). As expected, HIV symptoms correlated with the BDI somatic scale (r = 0.30, p < .001) but not with the BDI dysphoria items (r = -0.03). The distress factor score correlated moderately with the BDI somatic items (r = 0.51, p < .0001) but was associated to a greater magnitude with the BDI dysphoria scale (r = 0.66, p < .0001). Nevertheless, the distress model was recomputed including both BDI dysphoric and somatic items and was used in the same set of multiple regression analyses (testing viral burden as a moderator of the distress-immune relationships). Whether BDI somatic items were excluded or not, the pattern of findings from these analyses remained the same. Back

3Using this method (51), the original overall regression equation (A) is algebraically adjusted (B): (A) Y7predicted = b70 + b71X + b72Z + b73XZ; (B) Y7predicted = (b71 +b73Z)X + (b72Z + b70), where Y = outcome immune variable; X = predictor, distress; Z = moderator, HIV-1 viral load. To determine the relationship of the predictor on the outcome variable at different levels of the moderator, two values for the moderator are used. A "high" value of viral load is inserted into the equation, generating a new equation that estimates the degree to which distress predicts the immune outcome measure at the high level of viral load. The same process follows for a "low" value of viral load. The "high" and "low" viral load levels were set at 1 SD above and 1 SD below the mean. Back


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 DISCUSSION
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 ACKNOWLEDGMENTS
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