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Psychosomatic Medicine 67:798-806 (2005)
© 2005 American Psychosomatic Society

ORIGINAL ARTICLES

Sympathoimmune Anomalies Underlying the Response to Stressful Challenge in Human Immunodeficiency Virus Spectrum Disease

Barry E. Hurwitz, PhD, Kimberly A. Brownley, PhD, Sarosh J. Motivala, PhD, John R. Milanovich, PhD, Jeffrey L. Kibler, PhD, Lise Fillion, PhD, William G. LeBlanc, PhD, Mahendra Kumar, PhD, Nancy G. Klimas, MD, Mary Ann Fletcher, PhD and Neil Schneiderman, PhD

From the Behavioral Medicine Research Center (B.E.H., K.A.B., S.J.M., J.R.M., J.L.K., L.F., W.G.L., N.S.), Department of Psychology (B.E.H., K.A.B., S.J.M., J.R.M., J.L.K., L.F., N.S.), Department of Biomedical Engineering (B.E.H.), University of Miami, Miami, Florida; Division of Endocrinology and Metabolism (B.E.H., N.S.), Department of Psychiatry (M.K., N.S.), Department of Immunology and Microbiology (N.G.K., M.A.F.), School of Medicine, University of Miami, Miami, Florida.

Address correspondence and 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. E-mail bhurwitz{at}miami.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Objective: This study examined immune, endocrine, and cardiovascular reactivity during stressful behavioral challenge in human immunodeficiency virus (HIV) seropositive (HIV+) and seronegative (HIV–) men and women and assessed whether immunocellular reactivity was differentially associated with concomitant alterations in sympathetic response.

Methods: The 133 HIV+ [84 asymptomatic, 49 symptomatic] and 92 HIV– subjects completed a speech stress reactivity protocol.

Results: Immunocellular reactivity to the speech stressor did not differ among asymptomatic and symptomatic HIV+ groups; however, relative to seronegatives, reactivity differences were present. Specifically, HIV+ subjects exhibited greater increases in total number of T cells, as well as in cytotoxic/suppressor T cells, activated T cells, and activated cytotoxic/suppressor T cells, and less increase in natural killer (NK) cell numbers. In addition, less stress-induced increase in NK cell cytotoxicity was observed along with greater suppression of the lymphoproliferative response to mitogen stimulation in the HIV+ group. Although no group differences in catecholamine reactivity were observed, the association of immunoreactivity with catecholamine responsiveness differed between serostatus groups. Specifically, the HIV+ subjects compared with HIV– subjects displayed greater lymphocytosis per unit change in norepinephrine; whereas NK cell reactivity was positively related to epinephrine responsiveness, but only in the HIV– group. These findings were present even after controlling for age and body mass, as well as other potential influences on immunocellular migration, such as cortisol levels and prevailing cardiac output.

Conclusion: Early in HIV spectrum disease, functional abnormalities in the stress-induced migratory ability of specific immunocellular subsets are present that may reflect an underlying pathophysiological alteration in sympathoimmune communication.

Key Words: HIV • stress • cardiovascular • immune • catecholamines • sympathetic

Abbreviations: ACTH = adrenocorticotropin hormone; AIDS = acquired immunodeficiency syndrome; BMI = body mass index; C/S T cell = cytotoxic/suppressor T cell; cAMP-PKA = cyclic adenosine monophosphate-dependent protein kinase; CD38 = activation marker; CV = coefficient of variation; DBP = diastolic blood pressure; ECG = electrocardiogram; EPI = epinephrine; HIV = human immunodeficiency virus; HIV– = HIV seronegative; HIV+ = HIV seropositive; HIV+ A = HIV seropositive asymptomatic; HIV+ S = HIV seropositive symptomatic; HLA/DR = activation marker; ICG = impedance cardiogram; LPR = lymphocyte proliferation response; NE = norepinephrine; NK = natural killer; NKCC = natural killer cell cytotoxicity; PCG = phonocardiogram; PHA = phytohemagglutinin mitogen; SBP = systolic blood pressure; TPR = total peripheral resistance; {triangleup} = delta or change score.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHOD
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Among human immunodeficiency virus (HIV) seropositive (HIV+) individuals there is a wide variation in disease course; some develop symptoms rapidly, whereas others remain free of acquired immunodeficiency syndrome (AIDS) symptoms for long periods of time (ie, 10 to 20 years). The etiology of this variability remains unknown but may be due to some combination of biological and psychological factors. Laboratory methods that employ psychological challenges to elicit immunocellular responses may clarify pathophysiological links between psychological factors and diminished immunocompetence in HIV disease. For example, the stress reactivity paradigm, which involves presenting stressful stimuli and measuring various stressor-induced physiological changes that follow, has been used to provoke sympathetic activation and examine acute cardiovascular and enumerative and functional immunocellular responses in various healthy and patient populations (see 1,2). Common central autonomic pathways regulate cardiovascular and immune stress responses, which play a vital role in host protection (1,3). The immune system responds rapidly to a variety of stressors with increases in immunocellular trafficking to the circulation and possibly changes in immune function (4–7). The stress-induced immune system response is likely mediated by: (a) increased sympathetic input to lymphoid organs and tissues (3); (b) changes in circulatory dynamics acting on lymphoid tissues and the lymphocytes adhering to the vascular endothelium (8), and (c) prevailing cortisol levels, rather than to slower-acting changes in pituitary-adrenocorticotropin hormone (ACTH)-cortisol response (2,9,10).

The ability of the immune system to function depends in part on its ability to selectively mobilize an immunocellular migratory response via vascular and lymphatic systems (11). Understanding the association between stress and immune functioning in persons with immune-related disorders, such as HIV infection, remains a complex challenge because the extent of disease progression may affect the biomechanisms underlying this association. Disparities found in HIV+ as compared with HIV seronegative (HIV–) individuals, for instance, may represent a breakdown in the feedback mechanisms regulating CNS input, sympathetic activation, or endocrine outflow, on the one hand, and neuroimmunologic bidirectional communications on the other (12). Such disturbances may alter acute immune responding to environmental stressors via central-autonomic mediation and have long-term immunologic consequences. Assessing cardiovascular-immune and neuroendocrine-immune stress response relationships early in HIV disease progression, before AIDS diagnosis, may be important to understanding how stress affects immunological control before confounding disease complications and pathophysiology obscure their investigation.

Previously, we observed differences in speech stress-induced lymphocytosis of specific T cell subsets in a small sample of asymptomatic HIV+ and HIV– men (9). The present study sought to replicate these findings and to extend them to women, symptomatic pre-AIDS HIV+ individuals, and to other T cell subsets such as the cytotoxic/suppressor T cells (C/S T cells) that are negative for the phenotypic expression of the activation marker (CD38), which may be protective in long-term HIV survivors (13). By doing so within the context of prevailing cortisol levels, and concomitant stress-induced changes in indices of sympathetic and cardiovascular regulation, the present study may help to further describe HIV spectrum disease and the alteration of psychoneuroimmunologic regulation in relation to cardiovascular, endocrine, and autonomic functioning.


   METHOD
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Subjects
Two hundred forty-seven individuals, who were part of a larger study of biobehavioral indices of disease progression in pre-AIDS HIV infection (14,15), were examined in this study. Venous sampling difficulties reduced the final study sample to 225, of which 92 subjects were HIV– and 133 subjects were HIV+. Of the HIV+ subjects, 84 were HIV seropositive asymptomatic (HIV+ A) and 49 were HIV seropositive symptomatic (HIV+ S) but not AIDS-defined (16). The HIV+ subjects were recruited predominantly from outpatient services within the University of MiamiorMiami Veterans Administration Medical Center complex and through local HIV support service agencies, physician referrals, and advertisements in the surrounding Miami-Dade and Broward counties. Subjects were 18 to 45 years of age, with a minimum 8th-grade education. All women were premenopausal, not using hormonal contraceptives, and assessed nonsystematically throughout the menstrual cycle. AIDS-defined individuals were excluded to minimize potential confounding influences of more severe alterations in immunocompetence and symptomatology associated with disease progression. Other exclusionary criteria included (a) intravenous drug use in the past 6 months; (b) current use or history of alcohol or nonintravenous substance abuse or a positive urine toxicology screen; (c) history of heavy cigarette smoking (>50 pack years); (d) regular use in the past 3 months of medications with cardiovascular, neuroendocrine or immunomodulatory effects; (e) current major psychiatric disorder; (f) recent (<3 months) surgery requiring anesthesia, infection or chronic illness associated with immune alterations; (g) blood pressure >140/90 mm Hg; and (h) history of cardiorespiratory, diabetes mellitus, or other major disorders.

Procedures
Screening Session
After informed consent, subjects provided a brief oral medical history and underwent 12-lead electrocardiogram (ECG) and resting blood pressure evaluations. Urine and blood samples were collected for toxicological screening and to derive complete blood count, HIV serostatus using both enzyme-linked immunoassay and Western blot methods, and immune parameters. Qualified subjects were then scheduled for the reactivity session and given presession substance and exercise restriction instructions (14).

Reactivity Session
At 6 PM on the evening before the reactivity session, subjects reported to the General Clinical Research Center, were provided a light, caffeine-free dinner, and interviewed for compliance with presession restrictions, and a urine toxicology test was performed. Subjects then underwent autonomic function evaluation (see 14); at 7 AM the next day, after a light, caffeine-free breakfast, subjects were escorted to the Behavioral Medicine Research Center and instrumented for blood pressure and recording of ECG, impedance cardiogram (ICG), phonocardiogram (PCG), and respiration signals.

After the subject was seated, a heparinized catheter was inserted into a left forearm vein for the blood sample collection. Subjects then completed a 30-minute seated baseline rest period, followed by a videotaped evaluative speech task, and then a 40-minute posttask recovery period. The speech task, as previously described (17), required subjects to prepare (5 minutes) and present (5 minutes) a speech in which they were asked to defend themselves against the wrongful accusation of shoplifting. About 2 minutes before and after the task, subjects reported their perception of "threat," "stress," "challenge," and "control" associated with the speech stressor using the Subjective Appraisal Rating Scale (18).

During the baseline period, blood pressure measurements and ECG, ICG, PCG, and respiration signal recordings were collected at minutes 15, 16, 18, and 19, and blood samples were obtained during at minutes 14 and 17. During the 10-minute task period, blood pressure and physiological recordings were initiated each minute; and blood samples were collected during minutes 1, 3, 6, and 8. Throughout the posttask recovery period, blood pressure and physiological signals were obtained at 1 and 5 minutes and then at 5-minute intervals; blood samples were collected at 5, 10, 15, 25, and 40 minutes poststressor.

Measures
Immune Measures
The immune measures consisted of the following: (1) lymphocyte phenotypes using 3-color flow cytometry, determining percent and number of T cells and natural killer (NK) cells and subsets of these, using monoclonal antibodies specific for lineage using direct immunofluorescence techniques as described (15,19). This panel was used to determine number of helper/inducer T cells (CD3+CD4+), C/S T cells (CD3+CD8+), B cells (CD19+), and NK cells (CD56+CD3–CD8–). Expression of the HLA/DR and CD38 activation markers was also determined for CD3+ and CD8+ cells (15,20). The HIV viral load was determined using the ultrasensitive Amplicor reverse transcriptionorpolymerase chain reaction assay (Roche Diagnostics, Branchburg, NJ). Functional immune measures assessing natural killer cell cytotoxicity (NKCC) and T cell lymphocyte proliferation response (LPR) to the phytohemagglutinin mitogen (PHA) mitogen were also obtained. To derive the LPR, PHA stimulation at 10 µg/ml was tested using a whole blood method previously outlined (21). The mean of the 3 tests was derived and converted to cpm/100,000 cells and then normalized using log transformation. The NKCC against the K562 erythroleukemic cell target was measured for CD56+CD3– cells only in triplicate at 4 effector-to-target ratios, using a whole-blood chromium-release assay (21). Percent cytotoxicity was expressed on a 1-to-1 effector-to-target ratio.

Endocrine Measures
Plasma cortisol was quantified using a solid-phase 125I radioimmunoassay (Diagnostic Products, Los Angeles, CA). The inter- and intra-assay coefficients of variation (CVs) are <7% and <8%. Plasma ACTH was quantified using a highly sensitive Allegro immunoradiometric assay technique (Nichols, San Juan Capistrano, CA). The inter- and intra-assay CVs are <9% and <4.5%. The assay for plasma norepinephrine (NE) and epinephrine (EPI) uses high-pressure liquid chromatography with solvent delivery module (Model 5700, ESA Inc., Chelmsford, MA) and ESA HR-80 column (Model 5100, ESA Inc.) and electrochemical detection as described (22). The chromatographed NE and EPI were detected with an applied potential of 0.35 V on detector 1, 0.10 V on detector 2, and recorded from detector 3 with a potential of –0.30 V. Sample concentration was derived by internal standard peak area relative to peak areas of unknown NE or EPI ratio. Inter- and intra-assay CVs for NE are <6% and <3% and for EPI are <13% and <14%.

Cardiovascular Measures
The Critikon Dinamap Vital Signs automated blood pressure monitor (Model 1846SX, Johnson & Johnson, Tampa, FL) was used. Cardiac performance was assessed using previously described impedance cardiography methods to derive measures of stroke volume, heart rate, cardiac output, Heather Index of cardiac contractility, and total peripheral resistance (TPR) (23,24). Hematocrit values obtained during the session were used to estimate blood resistivity and used to calculate stroke volume.

Data Reduction and Statistical Analyses
The analysis focused on immune, endocrine, and cardiovascular responses at baseline and during speech presentation among the 3 subject groups (HIV–, HIV+ A, and HIV+ S). For each immune, endocrine and cardiovascular measure, mean values were computed for baseline and task periods. Mean task values were subtracted from mean baseline values to compute reactivity or {triangleup} scores. The analysis strategy examined: (1) differences in baseline, and stressor reactivity and subjective appraisal measures; and (2) whether mechanisms that influence immunocellular trafficking (ie, resting cortisol level, change in circulation indexed by cardiac output reactivity, and stress-induced sympathetic activation indexed by catecholamine reactivity) were differentially associated with the observed immunocellular reactivity.

The primary objective was accomplished using repeated-measures analyses of covariance (SAS Proc GLM, SAS Institute, Cary, NC) in a 2 (Period: baseline, speech) x 3 (Group: HIV–, HIV+ A, HIV+ S) design. Univariate analyses were then used to determine the source of significant interaction effects. Subsequent comparisons of least-squares means evaluated pairwise group differences. Age and body mass index (BMI), which are known to relate to cardiovascular and immune function, were included as covariates (2,24). The secondary objective was accomplished using multivariate regression analyses (SAS Proc REG). While controlling for age, BMI, resting CD4 count (as a marker of health status), and other relevant baseline immune measures, these analyses examined the extent to which the relationship between stress-induced immunocellular reactivity and potential factors known to influence immunocellular trafficking differed in HIV+ compared with HIV– subjects.1 Values for predictors were centered before analysis, sample size-adjusted influence diagnostics were used to evaluate outlier observations, and 2-tailed, {alpha} = 0.05 criteria were used to determine statistical significance.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
Sociodemographic and Clinical Group Characteristics
Study sample characteristics are presented in Table 1. The 3 groups were comparable in gender and ethnicity ({chi}2 = 2.5 and 6.7, respectively, p > .15), but differed in age and BMI [F(2,223) = 5.9 and 3.1, respectively, p < .05], and in education and income ({chi}2 = 16.1 and 18.6, respectively, p < .02). Subjects in the HIV– group were slightly younger and more likely to have a college degree and to earn more then $30,000 than those in both HIV+ groups (p < .03). HIV– subjects had lower BMI than HIV+ A (p < .02) but not HIV+ S subjects. About 73% of asymptomatic and 51% of symptomatic HIV+ subjects were not treated with anti-HIV medications (see Table 1). The remaining subjects were treated with antiretroviral medications with, respectively, 57% and 66% of these persons on monotherapy and the remaining on combination therapy. Compared with HIV+ A subjects, HIV+ S subjects were more likely to use anti-retroviral medications ({chi}2 = 6.3, p < .05). The HIV+ groups did not differ in viral load [F(1,128) = 1.5] or illness duration [F(1,119) = 2.7].


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  		TABLE 1. Sociodemographic and Clinical Characteristics of the Study Sample

 

Prestressor Levels of Immune, Endocrine, and Cardiovascular Measures
Baseline immune, endocrine, and cardiovascular measures are presented in Table 2. The Group main effect was significant for the CD3+, CD3+HLA/DR+, CD4+, CD8+NK–, CD8+HLA/DR+CD38+, CD8+HLA/DR+CD38–, B, and NK cell counts [F(2,219) = 4.0, 12.7, 76.9, 56.6, 45.9, 13.8, 11.5, and 11.3, respectively, p < .0003], and for the LPR [F(2,210) = 4.0, p < .02]. Baseline NKCC did not differ among groups. Pairwise comparisons indicated that: (1) compared with the HIV– group, both HIV+ groups exhibited fewer CD4+, B, and NK cells, and more CD8+NK–, CD8+HLA/DR+CD38+, and CD8+HLA/DR+CD38– cells (p < .001); (2) compared with the HIV+ A group, the HIV– group displayed fewer CD3+HLA/DR+cells (p < .0001), and the HIV+ S group displayed less CD3+, CD3+HLA/DR+, CD8+NK–, and CD8+HLA/DR+CD38– cell count (p < .03); and 3) compared with the HIV+ A group, the HIV– group displayed greater LPR (p < .006).


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  		TABLE 2. Mean ± SD Baseline Measures of Immune, Neuroendocrine, and Cardiovascular Levels

 

Significant Group differences were observed for diastolic blood pressure (DBP), TPR, cardiac output, stroke volume, the Heather index [F(2,219) = 3.2, 6.1, 2.9, 5.0 and 3.3, respectively, p < .04], and for EPI [F(2,217) = 3.1, p < .05] but not for NE, ACTH, or cortisol. Follow-up tests revealed that compared with the HIV– group, both HIV+ groups displayed greater DBP and TPR and more diminished stroke volume and cardiac contractility (p < .05), with a trend toward less cardiac output (p < .06). Although the difference was small, EPI level was greater in the HIV– than the HIV+ A group (p < .05).

Therefore, in sum, the HIV+ groups displayed: (1) diminished resting CD4, B, and NK cell counts, along with greater numbers of CD8 cells and activated CD8 cells; (2) decreased LPR; and (3) elevated DBP and TPR with diminished cardiac contractility, stroke volume, cardiac output, and EPI levels.

Reactivity to Speech Stress: Immune, Endocrine, and Cardiovascular Measures
Mean (±standard error) change in immune, endocrine, and cardiovascular responses to the speech stressor relative to prestressor levels, and their level of significance, are presented in Table 3. The Period x Group interaction was significant, indicating group differences in reactivity for the following measures: {triangleup}CD3+, {triangleup}CD3+HLA/DR+, {triangleup}CD8+NK–, {triangleup}CD8+HLA/DR+CD38+, {triangleup}CD8+HLA/DR+CD38–, and {triangleup}NK cells [respectively, F(2,211) = 8.8, 6.9, 17.7, 5.8, 5.5, and 10.5, p < .005], as well as for {triangleup}NKCC [F(2,196) = 3.8, p < .03] and {triangleup}LPR [F(2,203) = 5.5, p < .005]. Compared with the HIV– group, both HIV+ groups evidenced greater speech-induced increases in CD3+, CD3+HLA/DR+, CD8+NK–, and CD8+HLA/DR+CD38+ cells (p < .05); the CD8+HLA/DR+CD38– cell count increase was greater in the HIV+ A group than the HIV– group (p < .002). In contrast, the HIV+ groups displayed smaller increases in NK cells and NKCC than the HIV– group (p < .04) and a larger decrease in LPR (p < .05).


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  		TABLE 3. Mean (±SD) Change ({Delta}) Relative to Prestressor Baseline Levels in Immune, Neuroendocrine, and Cardiovascular Response to the Speech Stressor

 

The Period x Group effect was significant for {triangleup}systolic blood pressure (SBP) and {triangleup}DBP increases [F(2,222) = 3.6, 7.1, respectively, p < .03]; compared with the HIV– group, both HIV+ groups exhibited less SBP and DBP elevation during speech stress (p < .04). Although the {triangleup}TPR and {triangleup}cardiac output increased significantly during the stressor [Period effect, F(1,222) = 87.9 and 9.7, respectively, p < .003], these responses did not differ among groups. The Period x Group effects for {triangleup}stroke volume, and {triangleup}heart rate [F(2,222) = 6.4 and 10.7, respectively, p < .002] reflected differing magnitudes of response that countered each other, resulting in no differences in cardiac output reactivity (see Table 3). Therefore, the group differences in blood pressure reactivity were likely due to differences in reactivity of cardiac output in some subjects and TPR in others. Speech stress induced similar small cortisol [Period effect, F(1,217) = 13.8, p < .0003], and ACTH [F(1,217) = 3.7, p < .06] increases among groups.

Therefore, compared with the HIV– group, the HIV+ groups displayed (1) greater stress-induced increases in CD3+ and total activated (CD3+HLA/DR+) lymphocytes, and specifically in CD8+NK– and CD8+HLA/DR+CD38+ activated cells; (2) smaller stress-induced increases in NK cell number and NKCC; and (3) greater stress-induced suppression of the LPR. The HIV+ groups also exhibited smaller increases in blood pressure. However, these blood pressure differences were not explained by group differences in TPR reactivity or differences in heart rate and stroke volume responses, which countered each other; thus, blood pressure differences were presumably due to reduced cardiac output reactivity in some cases but reduced TPR reactivity in others. Therefore, in summary, among HIV+ subjects, the speech stressor induced enhanced T cell lymphocytosis in specific subsets but more blunted NK cell trafficking and NK cytolytic and T cell LPR function, with concomitant evidence of reduced blood pressure responsiveness.

Baseline and Poststressor Appraisal Ratings
Before the speech, subjects reported low to moderate mean ± SD levels of perceived stress (2.7 ± 1.7), threat (1.6 ± 1.1), challenge (4.0 ± 2.0), and control (4.2 ± 2.0), with HIV+ S subjects tending to report slightly higher perceived challenge (4.8 ± 1.9) than the HIV– (3.7 ± 1.9) and HIV+ A (3.9 ± 2.0) groups, [F(2,222) = 4.6, p < .02]. Overall, stress, threat, challenge, and control ratings increased after the speech [respectively, F(1,222) = 97.3, 27.4, 29.2, 19.2, p < .0001, with mean ± SD posttask values of 4.3 ± 2.0, 2.3 ± 1.7, 4.8 ± 1.9, 4.8 ± 1.9] but the increases did not differ across groups. The analysis of the relationship of stress-induced changes in appraisal with immunocellular reactivity revealed that {triangleup}CD4+ cells correlated inversely with change in perceived control (r = –0.14, p < .05), and {triangleup}NK cells inversely correlated with change in perceived stress (r = –0.17, p < .02). The relationship between perceived control and {triangleup}CD4+ cells was similar across HIV groups (r = –0.07 to –0.27). The relationship between perceived stress and {triangleup}NK cells, however, was stronger in the HIV– (r = –0.22, p < .04) and HIV+ A (r = 0.25, p < .03) groups than the HIV+ S group (r = 0.08). However, group differences in {triangleup}NK and NK count remained significant after controlling for stress-induced changes in perceived stress (p < .0001). Therefore, stressor-induced increases in stress appraisal did not account for group differences in immunocellular reactivity.

Relationships of Endocrine and Cardiovascular Mechanisms With Immunoreactivity
The majority of group differences in speech-induced immunoreactivity were due to HIV serostatus (ie, HIV+ versus HIV–) rather than one particular HIV+ subgroup. Therefore, the HIV+ groups were combined for the purpose of examining HIV-related differences in immune reactivity. Correlational analyses indicated that neither baseline cortisol nor {triangleup}cortisol was related to the immune reactivity for either HIV– or HIV+ subjects. However, {triangleup}cardiac output, {triangleup}NE, and {triangleup}EPI measures were significantly related to the measures of immune reactivity in both the HIV– (r = –0.40 to 0.42, p = .0001 to .05) and HIV+ (r = –0.28 to 0.43, p = .0001 to .05) groups. Thus, subsequent regression analyses used {triangleup}NE, {triangleup}EPI, and {triangleup}cardiac output as predictors of the immune responses to stress.

Predictors of Immunoreactivity During Speech Stress
The multivariate models testing main and interactive effects of HIV serostatus group {triangleup}NE, adjusting for age and BMI, accounted for 8% to 28% of the variance in {triangleup}CD3+, {triangleup}CD3+HLA/DR+, {triangleup}CD8+NK–, {triangleup}CD8+HLA/DR+CD38+, {triangleup}CD8+HLA/DR+CD38–, and {triangleup}NK cells [respectively, F(5,215) = 13.9, 7.7, 17.0, 5.1, 3.8, and 12.6, p < .003], and in {triangleup}NKCC [F(5,200) = 4.7, p < .0005] and {triangleup}LPR [F(5,207) = 4.8, p < .0004]. Models predicting {triangleup}CD4+and {triangleup}B cells were not significant. The {triangleup}NE main effect was significant for {triangleup}CD3+, {triangleup}CD8+NK–, {triangleup}LPA, {triangleup}NK, and {triangleup}NKCC (ßs ≥ 0.16, p < .04), indicating a direct impact of {triangleup}NE on these immune responses. In addition, the interaction of group and {triangleup}NE was significant for {triangleup}CD3+, {triangleup}CD3+HLA/DR+, {triangleup}CD8+NK–, and {triangleup}CD8+HLA/DR+CD38+ cells (ßs = 0.22 to 0.27, p < .02), indicating a difference in the relationship of {triangleup}NE with immunoreactivity for these 4 cell types in HIV– compared with HIV+ subjects. As seen in Figure 1, panels A and B, greater {triangleup}NE was associated with greater {triangleup}CD3+and {triangleup}CD8+NK– in both groups. However, as {triangleup}NE increased, the magnitude of {triangleup}CD3+ and {triangleup}CD8+NK– cells was greater in the HIV+ group than the HIV– group (ßs ≥ 0.28 versus < 0.11; difference of slopes, p < .005). In contrast, the relationship of {triangleup}NE to {triangleup}CD3+HLA/DR+ and to {triangleup}CD8+HLA/DR+CD38+ was significant only in the HIV+ group (ßs ≥ 0.21, p < .0005), indicating that the stress-induced increases in these cell types were linked to NE reactivity in HIV+ but not in HIV– subjects (see Figure 1, panel C). All of the interaction effects involving {triangleup}NE remained significant after controlling for baseline cortisol and the stress-induced changes in cardiac output and EPI; in addition, these findings were maintained when prestressor immune cell counts were controlled (p < .04).



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  		Figure 1. Regression lines depicting the relationship between speech-induced catecholamine (X axis) and immunocellular reactivity (Y axis) in the HIV-seronegative (closed circles) and HIV-seropositive (open squares) groups.

 

Models testing the effects of Group and {triangleup}EPI, adjusting for age and BMI, accounted for 6% to 15% of the variance in {triangleup}CD3+, {triangleup}CD3+HLA/DR+, {triangleup}CD8+NK–, {triangleup}CD8+HLA/DR+CD38–, and {triangleup}NK+cells [F(5,215) = 4.7, 2.6, 7.4, 3.2, and 7.8, respectively, p < .02], 6% of {triangleup}NKCC [F(5,200) = 2.3, p < .05], and 9% of {triangleup}LPR [F(5,207) = 4.3, p < .001]. The {triangleup}EPI main effect was significant for {triangleup}CD3+, {triangleup}LPA, and {triangleup}NK (ßs = –0.27 to 0.38, p < .03), indicating a direct impact of the EPI response on these immune responses. In addition, the interaction term was significant for {triangleup}NK (ß = –0.27, p < .02); {triangleup}NK was related to {triangleup}EPI in the HIV– group (ß = 0.17, p < .0008) but not in the HIV+ group (ß = 0.03) (see Figure 1, panel D). This interaction term remained significant after controlling for the effects of {triangleup}cardiac output, and baseline cortisol, and CD4 and NK cell counts (p < .05). Models predicting {triangleup}CD4+ and {triangleup}B cell reactivity were not significant.

Models testing the effects of Group and {triangleup}cardiac output, adjusting for age and BMI, accounted for 6% to 19% of the variance in {triangleup}CD3+, {triangleup}CD3+HLA/DR+, {triangleup}CD8+NK–, {triangleup}CD8+HLA/DR+CD38+, {triangleup}CD8+HLA/DR+CD38–, {triangleup}B, and {triangleup}NK+ cells [F(5,210) = 5.6, 3.6, 9.8, 3.1, 3.1, 2.7, and 9.1, respectively, p < .03], and 10% of {triangleup}LPR [F(5,202) = 4.4, p < .0008] and 10% of {triangleup}NKCC [F(5,195) = 4.5, p < .0007], but failed to predict {triangleup}CD4+. No interaction effects were significant.

Therefore, NE and EPI reactivity account for significant variance in immunocellular reactivity, and the effects of NE and EPI reactivity on immunocellular reactivity appear to be independent of one another and of cardiac output reactivity. Moreover, HIV+ differed from HIV– subjects in that NE reactivity had a heightened relationship with T cell trafficking, specifically CD8 and activated cells. In contrast, the positive relationship between NK and EPI reactivity that was observed in the HIV– subjects was not observed in the HIV+ subjects. The serostatus differences in catecholamine-immune relationships were maintained even after correcting for the influence of other factors including age, BMI, and the prevailing cortisol, and baseline immunocellular levels.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
The main finding of this study is that HIV infection in pre-AIDS individuals has disparate effects on immunocellular reactivity of particular cell subsets, but not on the CD4 cells, the cells primarily attacked by the infection. Despite differences in basal immune measures that were characteristic of persons in pre-AIDS stages (21,25), the groups were well matched, and the speech stressor resulted in comparable profiles of enumerative and functional immunocellular reactivity among groups. However, relative to the HIV– group, both HIV+ groups exhibited greater increases in T cell and CD8+ cell reactivity, including reactivity of activated T cells and in particular activated cytotoxic T cells with CD38+ phenotype. The HIV+ subjects also evidenced more blunted stress-induced increases in NK cell count and cytotoxicity and a larger suppression of T cell LPR. These serostatus differences in stress-induced immunocellular trafficking and function replicate and extend in a larger, more community-representative sample of both men and women those findings that we reported previously in a smaller sample of asymptomatic HIV+ men (9). The observed abnormalities in the relationship of these stress-induced changes in immunocellular trafficking with catecholamine response suggest that an underlying pathophysiological alteration in sympathoimmune communication may account for these findings.

Lymphoid organs and tissue are innervated by the sympathetic nervous system, thus establishing a direct path of communication for rapid autonomic control of immune system functioning (3). Lymphocytes and macrophages express ß2-adrenergic receptors, making them responsive to sympathetic neurotransmitters (eg, NE and EPI) causing a redistribution of leukocytes by detaching cells marginated in vessels and by mobilizing cells from lymphoid organs and tissues (11,26). The sympathetic neurotransmitters may facilitate these immunocellular alterations by increasing T lymphocyte, NK cell, and macrophage activity via induction of cyclic adenosine monophosphate-dependent protein kinase (cAMP-PKA) signaling (3,8,27). The ß2-adrenergic receptor densities on lymphocytes rapidly up- or down-regulate within minutes, depending on the prevailing or acute agonist level, and stress-induced lymphocytosis in healthy individuals is partially dependent on the propensity to be a high or low catecholamine responder to stress (28,29).

Consistent with previous studies, little or no difference in baseline catecholamines was observed among groups (22,30–32). However, compared with the HIV– subjects, HIV+ subjects displayed larger increases in various T cell reactivity measures (eg, total number of T cells, cytotoxic T cells, activated T cells, and activated cytotoxic T cells with the CD38+ phenotype) per given NE response. Sympathetic neuromediation of both cellular and humoral immunity has been confirmed with ß-adrenergic blockade studies showing attenuation of stress-induced NK cell activity and selective inhibition of CD4+ subset cytokine production (33–35). Studies infusing adrenergic agonists have documented the redistribution of lymphocyte subsets and alterations in immune function similar to what has been observed in this study ie, greater T cell (particularly CD8+, and CD38+ subsets) and more diminished NK–like T cell (ie, CD3+ cells that co-express CD16 and/or CD56) responsivity in HIV+ subjects (32). Other studies have shown that ß-adrenoceptor antagonism diminishes or blocks stress-induced immune responses and may do so based on lymphocyte adhesion molecule expression (26,34,36).

The HIV+ subjects in the present study displayed greater basal CD8 cell count and greater CD8 cell and activated CD8 cell mobilization in response to stress-induced sympathetic activation. The CD8 cell expansion and heightened responsivity reflects an immune system that is geared up to challenge infection and is particularly primed to adapt to stress with a highly mobile set of cytotoxic and noncytotoxic CD8 cells. The CD8+HLA/DR+CD38+ subset has been identified as having noncytotoxic properties and evidence indicates that it releases a cell antiviral factor to support host protection (13). The apparent up-regulation of the NE communication with these cells in these pre-AIDS individuals may be an adaptive compensatory mechanism present in earlier stages of disease.

In contrast, the HIV+ subjects in this study displayed diminished NK cell count at rest and diminished NK cell reactivity per given EPI response to speech stress, not unlike that reported by adrenergic infusion studies (31). The NK cells mediate cytotoxicity against target cells and are critical first responders against acute and chronic viral infection and malignant cells (37). Impaired NK–mediated immunity occurs in early stage HIV infection and is predictive of HIV progression (38,39). Previously, EPI has been shown to influence NK cell adhesion and promote NK cell migration into the circulation from peripheral blood, spleen, and lung stores (40). The present findings indicate an impaired ability to mobilize NK cells in HIV infected persons possibly due to disrupted EPI communication with this cell.

HIV groups also differed in cardiovascular reactivity. Specifically, despite having slightly greater resting blood pressure level, albeit within normal ranges, HIV+ subjects exhibited smaller speech-induced blood pressure reactivity compared with the HIV– subjects.2 Given the similar magnitude of catecholamine reactivity between groups, this finding would suggest that the HIV+ subjects may have more diminished {alpha}-adrenoceptor sensitivity or some abnormality in postreceptor function. In a previous report of a subset of HIV+ subjects from this study, who underwent autonomic testing using a standardized battery of simple cardiovascular reflex tests, autonomic function was largely intact (14). However, compared with HIV– and asymptomatic HIV+ subjects, the symptomatic HIV+ subjects displayed a diminished ability to sustain a blood pressure response during prolonged handgrip challenge. Thus, it appears that in addition to disruptions of sympathoimmune communication, the pre-AIDS stage is marked by some abnormality in both cardiac and vascular function that may be linked to some pathology of muscular or autonomic origin.

In the HIV-infected person, concerns about disease progression and long-term survival, stigma, and social mores that lead to prejudice and abandonment from one’s family and social network, depression, and anxiety are prominent (41,42). Previously, our laboratory reported elevations in state anxiety and cortisol levels and decreased NKCC and LPRs in persons awaiting notification of HIV test results (43). We have also observed the predictive association of psychological distress with diminished T-helper and B cell counts in pre-AIDS men and women (15). Although a link could not be established between group differences in stressor-related appraisals and immunocellular reactivity in this study, this finding does not imply that psychological distress is not etiologically related to the development of abnormalities in central-autonomic-immune function. Indeed, research by our group has shown that cognitive behavioral stress management can be effective in improving aspects of psychological and immunocellular status in HIV cohorts (44–46). Studies are ongoing to assess the effect of stress management on immunocellular reactivity in HIV spectrum disease.

In conclusion, this study is the most comprehensive examination to date of stress-induced changes in immunocellular trafficking and function in the context of simultaneous changes in sympathetic and hemodynamic functioning in a large, mixed gender, multiethnic, community-representative sample of HIV-infected persons and their noninfected counterparts. The major findings of this study suggest that relatively early in HIV disease, sympathetic regulation of the migratory redistribution from lymphoid structures to vascular circulation of specific immunocellular subsets is altered. For some immune cells, the communication appears to be enhanced and for other cells appears to be diminished. In each case, these sympathetic relationships were shown to be independent of prevailing levels of cortisol and magnitude of circulatory activation induced by the speech challenge, pre- and poststress appraisal of the stressful challenge, as well as other potential mitigating influences such as age, BMI, and basal cell numbers. Recent evidence indicates that levels of catecholamines may influence HIV disease progression. For example, in vitro NE and other cAMP-PKA humoral activators have been shown to facilitate HIV–1 replication (47,48). Moreover, in HIV+ persons classified with highly active autonomic function both at rest and by virtue of their responsiveness to stressful challenge, HAART therapy was less effective in suppressing viral load and in reconstituting CD4 cell count (49). Therefore, not only can sympathetic mediators play a role in disease progression, but the present findings suggest that the compensatory or decompensatory sympathoimmune adaptations of immunocellular trafficking may be a pathway by which the temporal course of disease is influenced. A limitation of this study is its cross-sectional design. Studies devised to prospectively evaluate changes in immune, endocrine, and cardiovascular functioning with HIV infection are needed to better understand etiological versus compensatory processes in disease progression. Moreover, the extent to which the chronic social and lifestyle burdens of HIV infection interact with the observed alterations in sympathoimmune communication may be highly relevant to this process (15).

We gratefully recognize the technical contributions of the following people to this study: Alejandro Cazzaniga, BA, Shawna Freshwater, PhD, Julie Graves, MS, Jessie Hatfield, BA, Karen Langman-Kuskin, RN, Pat Major, MD, and Maggie Olsen-Istel, BS.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 
1Correlational analyses were performed within each group (HIV+ A, HIV+ S, HIV–) to identify which of the potential factors (i.e., resting cortisol level and cardiac output, NE, and EPI reactivity) were associated with the stress-induced changes in immunoreactivity. The findings revealed no differences between the 2 HIV+ groups. Hence, the HIV+ A and HIV+ S groups were combined for the multiple regression analyses. Back

2The observed differences in cardiovascular resting function and stress-induced reactivity were not a consequence of lipodystrophy or metabolic syndrome due to treatment with protease inhibitor anti-HIV medications because these data were collected before widespread administration of these medications (i.e., 1993–1997). Most study subjects were not treated with anti-HIV medications, and no differences between HIV+ groups were observed in the typeof anti-HIV medication used (see Table 1). Back

This research was supported by a Research Grant (MH49548) and a Training Grant (MH18917) from the National Institute of Mental Health of the National Institutes of Health.

DOI:10.1097/01.psy.0000181279.06164.6e


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
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