Dysregulation of Inflammatory Processes as Dysregulation of Inflammatory Processes as a Potential Shared Pathophysiological a Potential Shared Pathophysiological

Mechanism Linking Neurocognitive and Mechanism Linking Neurocognitive and Behavioral Dysfunction in Persons with HIV, Behavioral Dysfunction in Persons with HIV,

Depression, and Chronic StressDepression, and Chronic Stress

Lydia Temoshok, Ph.D.Lydia Temoshok, Ph.D.lydia.temoshok@gmail.comlydia.temoshok@gmail.com

Invited lecture, Neuro-Infectious Disease Interest Group,

National Institutes of HealthNovember 18, 2015

PSYCHONEUROIMMUNOLOGY (PNI)PSYCHONEUROIMMUNOLOGY (PNI)Past, Present, and Future…Past, Present, and Future…

““Psyche and body react sympathetically to each Psyche and body react sympathetically to each other, it seems to me. A change in the state of the other, it seems to me. A change in the state of the psyche produces a change in the structure of the psyche produces a change in the structure of the body, and, conversely, a change in the structure of body, and, conversely, a change in the structure of the body produces a change in the state of the the body produces a change in the state of the psyche.” psyche.” - Aristotle: - Aristotle: Physiognomonica, Physiognomonica, 319 BC319 BC

““Psychoneuroimmunology is the transdisciplinary Psychoneuroimmunology is the transdisciplinary field concerned with interactions among behavior, field concerned with interactions among behavior, the immune system, and the nervous system.” the immune system, and the nervous system.”

- George F. Solomon, M.D., 1996- George F. Solomon, M.D., 1996

First Psychoimmunology Laboratory First Psychoimmunology Laboratory Studies: Amkraut & SolomonStudies: Amkraut & Solomon

Effects of neonatal handling on Effects of neonatal handling on immunity. immunity.

(Solomon, et al. (Solomon, et al. NatureNature 1968, 220: 821-23). 1968, 220: 821-23).

Inbred mice that spontaneously Inbred mice that spontaneously developed fighting behavior developed developed fighting behavior developed smaller tumors that were more likely to smaller tumors that were more likely to regress completely. regress completely.

(Amkraut & Solomon. (Amkraut & Solomon. Cancer Res. Cancer Res. 1972, 32: 1428-33).1972, 32: 1428-33).

PNI on the Map: “Classic” StudiesPNI on the Map: “Classic” Studies Behaviorally conditioned immunosuppression: Pair saccharin and Behaviorally conditioned immunosuppression: Pair saccharin and

cyclophosphamide; when conditioned rats get saccharin water, cyclophosphamide; when conditioned rats get saccharin water, they show they show significantly suppressed antibody response significantly suppressed antibody response vs. vs. unconditioned controls unconditioned controls (Ader & Cohen. (Ader & Cohen. Psychosom Med Psychosom Med 1975; 37: 1975; 37: 333-40)333-40)

Stress induced immunosuppression: Inescapable but not Stress induced immunosuppression: Inescapable but not escapable tail shock (yoked control model) suppresses lymphocyte escapable tail shock (yoked control model) suppresses lymphocyte proliferation to PHA, ConA. proliferation to PHA, ConA. (Laudenslager (Laudenslager et alet al. . ScienceScience 1983, 1983, 221: 862-4)221: 862-4)

Tumor rejection in rats after inescapable or escapable shock. Tumor rejection in rats after inescapable or escapable shock. (Visintainer (Visintainer et al. Scienceet al. Science 1982, 216: 437-9) 1982, 216: 437-9)

Psychoneuroendocrine influence (rotational stress—78 vs 33 rpm) Psychoneuroendocrine influence (rotational stress—78 vs 33 rpm) on immunocompetence and neoplasia. on immunocompetence and neoplasia. (Riley, V. (Riley, V. ScienceScience 1981, 1981, 212: 1100-9)212: 1100-9)

CNS

Immune cells

The Immune System is in Constant Communication with the Brain

Humoral Pathway

Neural Pathway

What is going on in the immune system impacts what is going on in the brain

The brain has an “immunostat” that enables it to perceive and form a sensory representation of what is going on in the immune system, using immune cell communication molecules (cytokines)

AnorexiaSleepLethargyCognitive deficitsFever

Slide courtesy of Dr. Keith W. Kelley, editor-in-chief, Brain Behavior & Immunity

Interactions with Individual DifferencesInteractions with Individual Differences In hamster melanoma model, after injecting tumor fraction, there is In hamster melanoma model, after injecting tumor fraction, there is

a significant main effect of shaking stress but also stress-behavior a significant main effect of shaking stress but also stress-behavior interaction; i.e., Significantly longer latency to tumor detection in interaction; i.e., Significantly longer latency to tumor detection in hamsters coded as “inactive-dominant” (standing ground) vs. hamsters coded as “inactive-dominant” (standing ground) vs. “activated-anxious” (scrambling). “activated-anxious” (scrambling). (Temoshok (Temoshok et alet al., ., Ann NY Acad Ann NY Acad SciSci 1987; 496: 501-509) 1987; 496: 501-509)

In rhesus macaques, “personality” and serotonin transporter In rhesus macaques, “personality” and serotonin transporter genotype interact with social context to affect immunity and viral genotype interact with social context to affect immunity and viral set-point in Simian Immunodeficiency Virus Disease: set-point in Simian Immunodeficiency Virus Disease: ““Joint risk factors:” neurogenetic characteristics, and sustained Joint risk factors:” neurogenetic characteristics, and sustained

submissive or aggressive “coping” in unstable social conditions submissive or aggressive “coping” in unstable social conditions were associated with more adverse immune outcomes. were associated with more adverse immune outcomes. (Capitanio (Capitanio et al.et al. Brain Behavior & ImmunityBrain Behavior & Immunity, 2010), 2010)

Interactionist Model of DiseaseInteractionist Model of DiseaseExample: “personality” X genotype X social context in macaquesExample: “personality” X genotype X social context in macaques

Social StressStable/ Unstable conditions

Genotype(serotonin transporter promotor –short allele associated with aggression/ anxiety under adverse conditions

“Personality” High/ Low Sociability

CopingAggression

Affiliation

Submission

Endocrine responsesCortisol

Immune responsesInnate – Type I interferon

Specific – T-cell activation; IgG

Disease outcomeSIV RNA

Viral set point

Adapted from: Capitanio et al. Brain Behavior & Immunity, 2010

CENTRALITY OF EMOTIONS: CENTRALITY OF EMOTIONS: At the Crossroads of Mind and BodyAt the Crossroads of Mind and Body Emotions are anchored in the physiology of Emotions are anchored in the physiology of

the brain.the brain. Primary emotions (anger, fear, sadness, joy, Primary emotions (anger, fear, sadness, joy,

shame) are closely connected with the limbic shame) are closely connected with the limbic systemsystem

More “cognitive” emotions (e.g., curiousity, guilt, More “cognitive” emotions (e.g., curiousity, guilt, pride) have more cerebral cortical connections.pride) have more cerebral cortical connections.

Emotions have multiple functions, which have Emotions have multiple functions, which have evolved over time through selection pressure.evolved over time through selection pressure.

EMOTIONAL IQ: THE ABILITY TO EMOTIONAL IQ: THE ABILITY TO ACCURATELY READ EMOTIONSACCURATELY READ EMOTIONS

In order to cope in complex social situations, it is In order to cope in complex social situations, it is important to “read” emotions in others as accurately important to “read” emotions in others as accurately as possible = “Emotional IQ.” as possible = “Emotional IQ.”

To survive/ gain power, etc. human sometimes tell To survive/ gain power, etc. human sometimes tell lies about their true emotions.lies about their true emotions.

The ability to lie convincingly but appropriately is The ability to lie convincingly but appropriately is sometimes called “diplomacy” (when noticed).sometimes called “diplomacy” (when noticed).

The ability to read when someone is lying is part of The ability to read when someone is lying is part of “emotional IQ.”“emotional IQ.”

EMOTIONAL DISPLAYS REGULATE EMOTIONAL DISPLAYS REGULATE SOCIAL INTERACTIONS SOCIAL INTERACTIONS

Emotional displays communicate important Emotional displays communicate important information to others, both friends and foe.information to others, both friends and foe.

In order to meet one’s physical and social In order to meet one’s physical and social needs, one has to express emotions clearly needs, one has to express emotions clearly and effectively and be understood. and effectively and be understood.

Increasing importance of facial expressions in Increasing importance of facial expressions in humans.humans.

Adaptiveness of “Negative” Emotions:Adaptiveness of “Negative” Emotions:Help Memory to Function Well Help Memory to Function Well

Searing of emotion into episodic memory is Searing of emotion into episodic memory is important for memory of context.important for memory of context.

If emotion is dissociated from events, these If emotion is dissociated from events, these memories will not be well-consolidated.memories will not be well-consolidated.

If emotion is repressed and not recognized, the If emotion is repressed and not recognized, the self-signaling power of negative emotions is self-signaling power of negative emotions is curtailed short of consciousness, so situations curtailed short of consciousness, so situations engendering them cannot be modified/resolvedengendering them cannot be modified/resolved

Adaptiveness of “Negative” Emotions:Adaptiveness of “Negative” Emotions:Regulation of Physiological Processes Regulation of Physiological Processes

Emotional phenomena are more Emotional phenomena are more responsive to environmental changes responsive to environmental changes than are reflexes.than are reflexes.

Importance of emotion, especially Importance of emotion, especially “negative emotions,” in helping “negative emotions,” in helping organisms adapt and self-regulate via organisms adapt and self-regulate via negative feedback.negative feedback.

Adaptiveness of “Positive” Emotions:Adaptiveness of “Positive” Emotions:Help Us Recognize What is Good for Us Help Us Recognize What is Good for Us Joy and other positive emotions are very reinforcing of Joy and other positive emotions are very reinforcing of

behaviors.behaviors.

Because of connections to brain’s “pleasure center,” Because of connections to brain’s “pleasure center,” reinforcing messages (e.g., related to sexual pleasure, reinforcing messages (e.g., related to sexual pleasure, eating) can be hijacked.eating) can be hijacked.

Result can be addictive behaviors where what is Result can be addictive behaviors where what is reinforced ISN’T good for us.reinforced ISN’T good for us.

Chemicals (drugs, food additives) derail feedback Chemicals (drugs, food additives) derail feedback systems and engender spiraling positive feedback loops.systems and engender spiraling positive feedback loops.

Emotional Recognition & Emotional Recognition & Expression Help Regulate Expression Help Regulate

Internal Homeostasis Internal Homeostasis

The Trouble with Being Too NiceThe Trouble with Being Too Nice

MODEL OF BIOBEHAVIORAL COPING ADAPTIVENESS

Time

Rea

ctiv

ity

Normal Homeostasis

Maladaptive 3

Maladaptive 1

Maladaptive 2: (e.g., perseverative thinking, rumination)

Stimulus

Temoshok, Annals NY Acad Sci 2000; 917: 446-455.

Analogies: A HypothesisAnalogies: A Hypothesis

Recognize problemRecognize problem Functional: identifyFunctional: identify problem correctlyproblem correctly Dysfunctional:Dysfunctional: denial/exaggeratedenial/exaggerate

Coping/ OutcomeCoping/ Outcome Functional: conflict Functional: conflict

resolution, rebalanceresolution, rebalance Dysfunctional: no Dysfunctional: no

resolution, chronic resolution, chronic stress/ panic, PTSDstress/ panic, PTSD

Recognize antigenRecognize antigen Functional: recognizeFunctional: recognize pathogen correctlypathogen correctly Dysfunctional:Dysfunctional: Signal Signal impairmentimpairment Coping/OutcomeCoping/Outcome Functional: neutralize Functional: neutralize

pathogen/ wound healingpathogen/ wound healing Dysfunctional: immune Dysfunctional: immune

incompetence, cancer/ auto-incompetence, cancer/ auto-immune disorders immune disorders

Central Nervous System Immune System

Insufficient Attention to Coping vs. Insufficient Attention to Coping vs. Stress in Most StudiesStress in Most Studies

The goal of coping is to adapt to changing internal and The goal of coping is to adapt to changing internal and environmental conditions, and to reestablish homeostasis. environmental conditions, and to reestablish homeostasis.

Coping is intrinsically related to the concept of “stress:” Coping is intrinsically related to the concept of “stress:” Successful or adaptive coping reduces stress, and Successful or adaptive coping reduces stress, and determines whether internal and external stimuli are determines whether internal and external stimuli are interpreted and function as stressors. interpreted and function as stressors.

Coping occurs across multiple systems: cognitive, emotional, Coping occurs across multiple systems: cognitive, emotional, behavioral, social, immunological, hormonal, cardiovascular, behavioral, social, immunological, hormonal, cardiovascular, etc.etc.

Persistent trait-like Individual differences in coping are Persistent trait-like Individual differences in coping are termed coping styles/ patterns/ proclivities in the termed coping styles/ patterns/ proclivities in the psychosocial domain, and response patterns in the psychosocial domain, and response patterns in the physiological realm.physiological realm.

COPING STYLE

Type A

Ada

ptiv

enes

s

Type C

Type B

High

Low

Temoshok, et al. Journal of Psychosomatic Research 1985; 29: 139-153.

HYPOTHETICAL MODEL: DYSREGULATED EMOTIONS ARE ASSOCIATED WITH DYSREGULATED

BIOLOGICAL PROCESSES AND NEGATIVE HEALTH OUTCOMES

Recognition and Expression of Negative Emotions

Eff

ects

on

Hea

lth

Type C Type A

Positive

Negative Type D

Type B“resilient”

Under-response to stress/pathogen

Over-response to stress/pathogenCardiovascular Disease Immune -mediated

disorders

repression suppression Over-expression

Appropriateexpression

Type C CopingType C Coping Type C is characterized by a fType C is characterized by a failure to recognize internal physical

or emotional cues, lack of emotional expression, focus on needs and feelings of others at the expense of self, façade of normalcy and mental health, underlying depression.

The Type C coping style has been found to be robust and The Type C coping style has been found to be robust and reproducible across different study populations, cultures (USA, reproducible across different study populations, cultures (USA, Italy), ethnic/racial groups, diseases studied (melanoma, HIV), Italy), ethnic/racial groups, diseases studied (melanoma, HIV), and measurement strategies (videotape rating, self-report/ and measurement strategies (videotape rating, self-report/ physiological discrepancies, Vignette Similarity Rating Method).physiological discrepancies, Vignette Similarity Rating Method).

This maladaptive coping pattern keeps the individual in a chronic This maladaptive coping pattern keeps the individual in a chronic state of stress with concomitant dysregulation of homeostatic state of stress with concomitant dysregulation of homeostatic responses, including responses, including inappropriateinappropriate responses to stressors, i.e., responses to stressors, i.e., increased physiological reactivity, and decreased recovery increased physiological reactivity, and decreased recovery (Temoshok, (Temoshok, Ann NY Acad Sci Ann NY Acad Sci 2000).2000).

LACK OF SYNCHRONY BETWEEN PHYSIOLOGY AND PSYCHOLOGY IN HIGH TYPE C INDIVIDUALS

PhysiologicalResponse

Psychological response

StressorTime

Kneier & Temoshok, J Psychosom Res 1984

Type C and Prognostic Indicators Type C and Prognostic Indicators (Biomarkers) in Malignant Melanoma(Biomarkers) in Malignant Melanoma

Temoshok. Soc Sci Med 1985; 20: 833-40.Temoshok. Soc Sci Med 1985; 20: 833-40.

Stronger Type C coping is associated with Stronger Type C coping is associated with significantly lower number of lymphocytes at significantly lower number of lymphocytes at primary tumor site (positive prog. indicator).primary tumor site (positive prog. indicator).

Stronger Type C coping associated with Stronger Type C coping associated with significantly higher mitotic rate of the cancer significantly higher mitotic rate of the cancer (negative prognostic indicator).(negative prognostic indicator).

Cf. current studies pioneered by Susan Cf. current studies pioneered by Susan Lutgendorf on tumor microenvironment.Lutgendorf on tumor microenvironment.

Individual Differences and HIVIndividual Differences and HIV

The considerable variability in HIV disease The considerable variability in HIV disease progression cannot be accounted for entirely by progression cannot be accounted for entirely by treatment, adherence, or genotype, and may be treatment, adherence, or genotype, and may be related to stress and/or stable individual differences.related to stress and/or stable individual differences.

PNI researchers over the past 20 years have PNI researchers over the past 20 years have suggested several individual difference factors that suggested several individual difference factors that may contribute to faster or slower HIV progression may contribute to faster or slower HIV progression or non-progression. or non-progression.

Individual difference factors may explain why some Individual difference factors may explain why some HIV+ people are “elite controllers” (non-progressors, HIV+ people are “elite controllers” (non-progressors, long-term survivors) or rapid progressors.long-term survivors) or rapid progressors.

Early Study: Early Study: HR Response & AIDS SurvivalHR Response & AIDS Survival

In 28 patients with AIDS, In 28 patients with AIDS,

heart rate response (to heart rate response (to describing 5 emotional describing 5 emotional situations over the past situations over the past week) which better week) which better approximated the inverted-U approximated the inverted-U shaped curve of normal shaped curve of normal homeostasis significantly homeostasis significantly predicted months survival.* predicted months survival.* The other 3 hypothetically The other 3 hypothetically maladaptive patterns had maladaptive patterns had significantly shorter significantly shorter survival. survival.

Temoshok et al. 1987.Temoshok et al. 1987.

Type C and HIV ProgressionType C and HIV Progression

In an Italian cohort (N = 200), Type C coping style significantly predicted HIV progression (from CDC-A2 to any more advanced stage) at 6 month (β = .32; R = .20; p < .01) and 12 month (β = .23; R = .17; p < .02) follow-up assessments.

Solano, Costa, Temoshok, Solano, Costa, Temoshok, et al.et al. Psychology & HealthPsychology & Health 2002; 17: 641-655. 2002; 17: 641-655.

Elucidating Biopsychosocial Mediators Elucidating Biopsychosocial Mediators of HIV Progressionof HIV Progression

Funded by NIH R01 grant # R01HD048154, L. Temoshok, P.I.Funded by NIH R01 grant # R01HD048154, L. Temoshok, P.I.

Temoshok et al. Brain, Behavior, and Immunity 2008, 2012, 2014Temoshok et al. Brain, Behavior, and Immunity 2008, 2012, 2014

Temoshok et al. Journal of Acquired Immune Def. Synd. 2009 Temoshok et al. Journal of Acquired Immune Def. Synd. 2009

Temoshok et al. Annals of Behavioral Medicine 2009, Temoshok et al. Annals of Behavioral Medicine 2009,

Temoshok et al. Psychosomatic Medicine 2010Temoshok et al. Psychosomatic Medicine 2010

Longitudinal Study OverviewLongitudinal Study Overview■■ 5+ year NIH R01 study5+ year NIH R01 study to identify the complex to identify the complex

mechanisms by which coping and interrelated mechanisms by which coping and interrelated psychosocial variables may interact with psychosocial variables may interact with immunological factors and physiological response immunological factors and physiological response patterns to affect HIV progression.patterns to affect HIV progression.

■ ■ 200 HIV+ participants (49% men, 92% African 200 HIV+ participants (49% men, 92% African American in HIV primary care clinic in inner city American in HIV primary care clinic in inner city Baltimore. Baltimore.

■ ■ 69% currently prescribed ART69% currently prescribed ART■ ■ 25% on cardiovascular medications, primarily for 25% on cardiovascular medications, primarily for

high blood pressurehigh blood pressure■ ■ 34% on psychiatric medications, primarily 34% on psychiatric medications, primarily

antidepressantsantidepressants■ ■ 17% on methadone maintenance17% on methadone maintenance

Laboratory MethodsLaboratory Methods A number of studies suggest that stress can enhance A number of studies suggest that stress can enhance

production of proinflammatory cytokines, notably production of proinflammatory cytokines, notably interleukin-6. interleukin-6. Dysregulation of the pro- and anti-inflammatory balance has Dysregulation of the pro- and anti-inflammatory balance has

been implicated in immune activationbeen implicated in immune activation and HIV pathogenesisand HIV pathogenesis Peripheral blood samples were drawn approximately one week Peripheral blood samples were drawn approximately one week

before the psychophysiology tasks.before the psychophysiology tasks. In vitroIn vitro production of IL-6, MIP-1 production of IL-6, MIP-1αα, and MIP-1, and MIP-1ββ was measured was measured

in response to three antigens: Candida, PHA, and p24 (HIV in response to three antigens: Candida, PHA, and p24 (HIV core protein). core protein).

Assays for MIP-1Assays for MIP-1αα and MIP-1 and MIP-1ββ performed by ELISA. performed by ELISA. Stimulation Index (SI): Antigen-induced chemokine production Stimulation Index (SI): Antigen-induced chemokine production

compared to unstimulated background controls.compared to unstimulated background controls.

Psychosocial Measures: AlexithymiaPsychosocial Measures: Alexithymia A personality construct that denotes a deficit in the cognitive A personality construct that denotes a deficit in the cognitive

processing and regulation of emotion.processing and regulation of emotion.

Similar to Type C coping in having difficulties identifying, Similar to Type C coping in having difficulties identifying, differentiating, and expressing emotions; i.e., dysregulation.differentiating, and expressing emotions; i.e., dysregulation.

Difficulty distinguishing emotions and physiological Difficulty distinguishing emotions and physiological sensations.sensations.

Unlike Type C in reporting an undifferentiated, diffuse Unlike Type C in reporting an undifferentiated, diffuse psychological distress, which fosters a hypervigilance toward psychological distress, which fosters a hypervigilance toward somatic sensations and increased report of somatic somatic sensations and increased report of somatic complaints (which high Type C copers do not report).complaints (which high Type C copers do not report).

Believed to be a predisposing factor for the development of Believed to be a predisposing factor for the development of medically unexplained symptoms and somatoform disorders.medically unexplained symptoms and somatoform disorders.

Psychophysiology MethodsPsychophysiology Methods Participants complete two emotion-induction Participants complete two emotion-induction

tasks approximately one week after each blood tasks approximately one week after each blood draw.draw.

Each 3-minute task is preceded by a 5-minute Each 3-minute task is preceded by a 5-minute resting baseline and followed by a 5-minute resting baseline and followed by a 5-minute resting recovery period.resting recovery period.

Heart rate and blood pressure are monitored at Heart rate and blood pressure are monitored at 90-second intervals.90-second intervals.

Variables of interest include reactivity during the Variables of interest include reactivity during the test period and return to baseline during the test period and return to baseline during the recovery period.recovery period.

Baseline regression analyses of Type C and Baseline regression analyses of Type C and alexithymia to MIP-1alexithymia to MIP-1αα and IL-6 production and IL-6 production

Temoshok Temoshok et al. Brain Behavior & Immunityet al. Brain Behavior & Immunity 2008 2008

Predictors

Dependent Variables: Antigen-stimulated cytokine production (Standardized Regression Coefficients, controlled for CD4+ count and age)

MIP-1α to p24

IL-6 to p24

IL-6 to PHA

IL-6 to Candida

Type C β = 0.102 r2 = .011

p = n.s.

β = 0.138 r2 = .019

p = .07

β = 0.182 r2 = .033 p = .018

β = 0.207 r2 = .042

p = .007

Alexithymia

β = -0.196 r2 = .039

p = .008

β = -0.065 r2 = .004

p = n.s.

β = 0.079 r2 = .007

p = n.s.

β = -0.014 r2 < .001

p = n.s.

N of cases 184 171 171 171

Linear regression analyses of alexithymia and Linear regression analyses of alexithymia and heart rate variables to p24 MIP-1heart rate variables to p24 MIP-1αα production production

Temoshok Temoshok et al. Brain Behavior Immunityet al. Brain Behavior Immunity 2008 2008

After adjustment for age, After adjustment for age, CD4+ count, CD4+ count, cardiovascular cardiovascular medications, and medications, and methadone use, higher methadone use, higher alexithymia, greater HR alexithymia, greater HR reactivity, and poorer HR reactivity, and poorer HR recovery (collapsed recovery (collapsed across tasks) were across tasks) were associated with less associated with less MIP-MIP-11αα production to the p24 production to the p24 antigen.antigen.

Predictors Dependent Variable: MIP-1α to p24Standardized

Regression Coefficients Alexithymia β = -.322 r2 = .11

p < .001*

Heart Rate Reactivity

β = -.224 r2 = .05

p = .01*

Heart Rate Recovery

β = -.188 r2 = .04

p = .03*

N of cases 140

Baseline Blood Pressure Reactivity Predicts Baseline Blood Pressure Reactivity Predicts Stimulated MIP-1Stimulated MIP-1ββ Production at 24 Months Production at 24 Months

After adjustment for After adjustment for age, CD4 count at age, CD4 count at baseline, baseline, cardiovascular cardiovascular medications, and medications, and methadone use, methadone use, greater SBP and DBP greater SBP and DBP reactivity during the reactivity during the Anger Recall Task at Anger Recall Task at baseline predicted baseline predicted reduced p24 reduced p24 stimulated MIP-1stimulated MIP-1ββ production at 24 production at 24 months.months.

Predictors β p r2

SBP reactivity and MIP-1β (Anger Recall)

-.293 .020* .085

DBP reactivity and MIP-1β(Anger Recall)

-.281 .027* .077

Baseline Blood Pressure Recovery Predicts Baseline Blood Pressure Recovery Predicts Stimulated MIP-1Stimulated MIP-1ββ Production at 24 Months Production at 24 Months

After adjustment for age, After adjustment for age, CD4 count at baseline, CD4 count at baseline, cardiovascular cardiovascular medications, and medications, and methadone use, higher methadone use, higher SBP and DBP during the SBP and DBP during the recovery period (i.e., recovery period (i.e., poorer recovery) poorer recovery) following the Anger following the Anger Recall Task at baseline, Recall Task at baseline, predicted reduced p24 predicted reduced p24 stimulated MIP-1stimulated MIP-1ββ production at 24 months.production at 24 months.

Predictors β p r2

SBP Recovery and MIP-1β (Anger Recall )

-.281 .033* .073

DBP Recovery and MIP-1β(Anger Recall )

-.268 .044* .065

Linear Analysis (GEE) of Chemokines at 36 Months, Linear Analysis (GEE) of Chemokines at 36 Months, Predicted by Baseline Type C Coping and AlexithymiaPredicted by Baseline Type C Coping and Alexithymia

Standardized regression coefficients calculated using SPSS Generalized Estimating Equation (GEE) algorithm, and probabilities for tests of null hypotheses, controlled for age at baseline, and CD4+ count, and number of missed medication doses at baseline and 36 months.

Predictors (at baseline)

Dependent

MIP-1α to p24

variables

IL-6 to p24

at 36 months

IL-6 to Candida IL-6 to PHA

Type C ** β= 0.164 p < .004

β= 0.130 p < .029

β= 0.099 p < .080

β= 0.122 p < .043

Alexithymia β= -0.150 p < .002

β= -0.150 p < .004

β= -0.112 p < .023

β= 0.164 ns

247 person observations

Linear Analysis (GEE) of Chemokines at 36 Months, Linear Analysis (GEE) of Chemokines at 36 Months, Predicted by Baseline Heart Rate Reactivity and RecoveryPredicted by Baseline Heart Rate Reactivity and Recovery

Predictors (at baseline)

Dependent variables

MIP-1α to p24

at 36 months

MIP-1β to p24

Heart Rate Reactivity

β= -0.22 p < .057

β= 0.092 ns

Heart Rate Recovery

β= -0.039 ns

β= -0.216 p < .074

Standardized regression coefficients calculated using SPSS Generalized Estimating Equation (GEE) algorithm, and probabilities for tests of null hypotheses, controlled for age at baseline, and CD4+ count, methadone use, and antihypertension medication at baseline and 36 months.

209 person observations

SummarySummary Baseline findingsBaseline findings: Stress sustained as a result of : Stress sustained as a result of emotional and emotional and

autonomic dysregulationautonomic dysregulation (alexithymia, Type C coping, (alexithymia, Type C coping, overreactivity) was associated with overreactivity) was associated with immune dysregulationimmune dysregulation, , characterized by enhanced immune activating IL-6 production characterized by enhanced immune activating IL-6 production (stress shown to activate innate inflammation signaling (stress shown to activate innate inflammation signaling pathways), and decreased anti-HIV pathways), and decreased anti-HIV ββ-chemokine-chemokine production. production.

Follow-up findingsFollow-up findings: Consistent with hypotheses and baseline : Consistent with hypotheses and baseline results, Type C coping predicted more IL-6 production at all (12, results, Type C coping predicted more IL-6 production at all (12, 18, 24, 36, and 48-month follow-up points18, 24, 36, and 48-month follow-up points). ).

A chronic pattern of physiological dysregulation, synergistic with A chronic pattern of physiological dysregulation, synergistic with emotional dysregulation, predicted persistent suppression of anti-emotional dysregulation, predicted persistent suppression of anti-HIV HIV ββ-chemokine production, which contributes to HIV -chemokine production, which contributes to HIV progression.*progression.*

* All results statistically controlled for ART and other medication usage * All results statistically controlled for ART and other medication usage and adherence.and adherence.

Key ConceptsKey Concepts Balance, e.g., pro-inflammatory and anti-Balance, e.g., pro-inflammatory and anti-

inflammatory cytokines.inflammatory cytokines. Homeostasis: inverted U , diurnal cortisol slope Homeostasis: inverted U , diurnal cortisol slope

and metastatic cancer outcomes.and metastatic cancer outcomes. Coherence and Synchronicity across systems.Coherence and Synchronicity across systems. Appropriateness of response:Appropriateness of response:

Immune activation to a psychological stressor Immune activation to a psychological stressor is not appropriate!is not appropriate!

Another example: the inappropriately Another example: the inappropriately activated (“promiscuous”) but ineffective activated (“promiscuous”) but ineffective response of the immune system to early HIV response of the immune system to early HIV infection, and immune over-activation.infection, and immune over-activation.

Longitudinal Study ConclusionsLongitudinal Study Conclusions

■ ■ ResultsResults suggest that dysregulated HIV-specific suggest that dysregulated HIV-specific cytokine (IL-6) production is associated with cytokine (IL-6) production is associated with Type C coping and may contribute to Type C coping and may contribute to mechanisms mediating previously documented mechanisms mediating previously documented negative effects on HIV progression.negative effects on HIV progression.

Biopsychosocial interventionsBiopsychosocial interventions to change Type C to change Type C coping and to promote regulated physiology and coping and to promote regulated physiology and immune function may also contribute to slowing immune function may also contribute to slowing HIV progression.HIV progression.

RecommendationsRecommendations Much PNI research has documented links between Much PNI research has documented links between

depression and increased levels of IL-6. depression and increased levels of IL-6. But to the extent high Type C copers do not But to the extent high Type C copers do not

recognize and/or do not acknowledge their recognize and/or do not acknowledge their underlying depression, they are unlikely to seek or underlying depression, they are unlikely to seek or follow through with mental health referrals.follow through with mental health referrals.

Therefore, we need innovative methods to identify Therefore, we need innovative methods to identify Type C copers, and innovative biopsychosocial Type C copers, and innovative biopsychosocial interventions to help them change dysfunctional interventions to help them change dysfunctional Type C coping and its underlying depression.Type C coping and its underlying depression.

Can we ameliorate maladaptive coping to positively Can we ameliorate maladaptive coping to positively impact mediators of HIV progression?impact mediators of HIV progression?

Identify factors to incorporate into bio-Identify factors to incorporate into bio-psychosocial interventions intended to influence psychosocial interventions intended to influence more salutary HIV medical outcomes.more salutary HIV medical outcomes.

Test these interventions for their ability to Test these interventions for their ability to (a) increase more adaptive coping, and (a) increase more adaptive coping, and (b) decrease emotional and physiological (b) decrease emotional and physiological dysregulation dysregulation which, hypothetically, will also decrease immune which, hypothetically, will also decrease immune

dysregulation, particularly inappropriate dysregulation, particularly inappropriate activation and inflammatory responses.activation and inflammatory responses.