This document discusses the potential shared pathophysiological mechanism of dysregulated inflammation linking neurocognitive and behavioral dysfunction in individuals with HIV, depression, and chronic stress. It provides background on psychoneuroimmunology and highlights classic studies showing interactions between behavior, the immune system, and nervous system. Emotions are discussed as being central to these interactions through their physiological effects in the brain and ability to aid memory formation and physiological regulation. Individual differences, genetics, and social contexts can impact these psychoneuroimmunological relationships.

1. Dysregulation of Inflammatory ProcessesDysregulation of Inflammatory Processes
as a Potential Shared Pathophysiologicalas a Potential Shared Pathophysiological
Mechanism Linking Neurocognitive andMechanism 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 Health
November 18, 2015

2. PSYCHONEUROIMMUNOLOGY (PNI)PSYCHONEUROIMMUNOLOGY (PNI)
Past, Present, and Future…Past, Present, and Future…
 ““Psyche and body react sympathetically to eachPsyche and body react sympathetically to each
other, it seems to me. A change in the state of theother, it seems to me. A change in the state of the
psyche produces a change in the structure of thepsyche produces a change in the structure of the
body, and, conversely, a change in the structure ofbody, and, conversely, a change in the structure of
the body produces a change in the state of thethe body produces a change in the state of the
psyche.”psyche.” - Aristotle:- Aristotle: Physiognomonica,Physiognomonica, 319 BC319 BC
 ““Psychoneuroimmunology is the transdisciplinaryPsychoneuroimmunology 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

3. First Psychoimmunology LaboratoryFirst Psychoimmunology Laboratory
Studies: Amkraut & SolomonStudies: Amkraut & Solomon
 Effects of neonatal handling onEffects of neonatal handling on
immunity.immunity.
(Solomon, et al.(Solomon, et al. NatureNature 1968, 220: 821-23).1968, 220: 821-23).
 Inbred mice that spontaneouslyInbred mice that spontaneously
developed fighting behavior developeddeveloped fighting behavior developed
smaller tumors that were more likely tosmaller 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).

4. PNI on the Map: “Classic” StudiesPNI on the Map: “Classic” Studies
 Behaviorally conditioned immunosuppression: Pair saccharinBehaviorally conditioned immunosuppression: Pair saccharin
andand cyclophosphamide; when conditioned rats get saccharincyclophosphamide; when conditioned rats get saccharin
water, they showwater, they show significantly suppressed antibody responsesignificantly suppressed antibody response
vs. unconditioned controlsvs. unconditioned controls (Ader & Cohen.(Ader & Cohen. Psychosom MedPsychosom Med
1975; 37: 333-40)1975; 37: 333-40)
 Stress induced immunosuppression: Inescapable but notStress induced immunosuppression: Inescapable but not
escapable tail shock (yoked control model) suppressesescapable tail shock (yoked control model) suppresses
lymphocyte proliferation to PHA, ConA.lymphocyte proliferation to PHA, ConA. (Laudenslager(Laudenslager et alet al..
ScienceScience 1983, 221: 862-4)1983, 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 33Psychoneuroendocrine influence (rotational stress—78 vs 33
rpm) on immunocompetence and neoplasia.rpm) on immunocompetence and neoplasia. (Riley, V.(Riley, V.
ScienceScience 1981, 212: 1100-9)1981, 212: 1100-9)

5. 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)
Anorexia
Sleep
Lethargy
Cognitive deficits
Fever
Slide courtesy of
Dr. Keith W. Kelley,
editor-in-chief, Brain
Behavior & Immunity

6. Interactions with Individual DifferencesInteractions with Individual Differences
 In hamster melanoma model, after injecting tumor fraction,In hamster melanoma model, after injecting tumor fraction,
there is a significant main effect of shaking stress but alsothere is a significant main effect of shaking stress but also
stress-behavior interaction; i.e., Significantly longer latencystress-behavior interaction; i.e., Significantly longer latency
to tumor detection in hamsters coded as “inactive-dominant”to tumor detection in hamsters coded as “inactive-dominant”
(standing ground) vs. “activated-anxious” (scrambling).(standing ground) vs. “activated-anxious” (scrambling).
(Temoshok(Temoshok et alet al.,., Ann NY Acad SciAnn NY Acad Sci 1987; 496: 501-509)1987; 496: 501-509)
 In rhesus macaques, “personality” and serotonin transporterIn rhesus macaques, “personality” and serotonin transporter
genotype interact with social context to affect immunity andgenotype interact with social context to affect immunity and
viral set-point in Simian Immunodeficiency Virus Disease:viral set-point in Simian Immunodeficiency Virus Disease:
 ““Joint risk factors:” neurogenetic characteristics, andJoint risk factors:” neurogenetic characteristics, and
sustained submissive or aggressive “coping” in unstablesustained submissive or aggressive “coping” in unstable
social conditions were associated with more adversesocial conditions were associated with more adverse
immune outcomes.immune outcomes. (Capitanio(Capitanio et al.et al. Brain Behavior &Brain Behavior &
ImmunityImmunity, 2010), 2010)

7. Interactionist Model of DiseaseInteractionist Model of Disease
Example: “personality” X genotype X social context in macaquesExample: “personality” X genotype X social context in macaques
Social
Stress
Stable/
Unstable
conditions
Genotype
(serotonin transporter
promotor –short allele
associated with aggression/
anxiety under adverse
conditions
“Personality”
High/ Low
Sociability
Coping
Aggression
Affiliation
Submission
Endocrine
responses
Cortisol
Immune
responses
Innate – Type I
interferon
Specific – T-cell
activation; IgG
Disease
outcome
SIV RNA
Viral set point
Adapted from:
Capitanio et
al. Brain
Behavior &
Immunity,
2010

8. 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 ofEmotions 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 limbicshame) 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 haveEmotions have multiple functions, which have
evolved over time through selection pressure.evolved over time through selection pressure.

9. EMOTIONAL IQ: THE ABILITY TOEMOTIONAL IQ: THE ABILITY TO
ACCURATELY READ EMOTIONSACCURATELY READ EMOTIONS
 In order to cope in complex social situations, it isIn order to cope in complex social situations, it is
important to “read” emotions in others as accuratelyimportant to “read” emotions in others as accurately
as possible = “Emotional IQ.”as possible = “Emotional IQ.”
 To survive/ gain power, etc. human sometimes tellTo survive/ gain power, etc. human sometimes tell
lies about their true emotions.lies about their true emotions.
 The ability to lie convincingly but appropriately isThe 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 ofThe ability to read when someone is lying is part of
“emotional IQ.”“emotional IQ.”

10. EMOTIONAL DISPLAYS REGULATEEMOTIONAL DISPLAYS REGULATE
SOCIAL INTERACTIONSSOCIAL INTERACTIONS
 Emotional displays communicate importantEmotional 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 socialIn order to meet one’s physical and social
needs, one has to express emotions clearlyneeds, one has to express emotions clearly
and effectively and be understood.and effectively and be understood.
 Increasing importance of facial expressions inIncreasing importance of facial expressions in
humans.humans.

11. Adaptiveness of “Negative” Emotions:Adaptiveness of “Negative” Emotions:
Help Memory to Function WellHelp Memory to Function Well
 Searing of emotion into episodic memory isSearing of emotion into episodic memory is
important for memory of context.important for memory of context.
 If emotion is dissociated from events, theseIf 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,If emotion is repressed and not recognized,
the self-signaling power of negative emotionsthe self-signaling power of negative emotions
is curtailed short of consciousness, sois curtailed short of consciousness, so
situations engendering them cannot besituations engendering them cannot be

12. Adaptiveness of “Negative” Emotions:Adaptiveness of “Negative” Emotions:
Regulation of Physiological ProcessesRegulation of Physiological Processes
 Emotional phenomena are moreEmotional phenomena are more
responsive to environmental changesresponsive to environmental changes
than are reflexes.than are reflexes.
 Importance of emotion, especiallyImportance of emotion, especially
“negative emotions,” in helping“negative emotions,” in helping
organisms adapt and self-regulate viaorganisms adapt and self-regulate via
negative feedback.negative feedback.

13. Adaptiveness of “Positive” Emotions:Adaptiveness of “Positive” Emotions:
Help Us Recognize What is Good for UsHelp Us Recognize What is Good for Us
 Joy and other positive emotions are very reinforcingJoy and other positive emotions are very reinforcing
of behaviors.of behaviors.
 Because of connections to brain’s “pleasureBecause of connections to brain’s “pleasure
center,” reinforcing messages (e.g., related tocenter,” reinforcing messages (e.g., related to
sexual pleasure, eating) can be hijacked.sexual pleasure, eating) can be hijacked.
 Result can be addictive behaviors where what isResult can be addictive behaviors where what is
reinforced ISN’T good for us.reinforced ISN’T good for us.
 Chemicals (drugs, food additives) derail feedbackChemicals (drugs, food additives) derail feedback

14. Emotional Recognition &Emotional Recognition &
Expression Help RegulateExpression Help Regulate
Internal HomeostasisInternal Homeostasis
The Trouble with Being Too NiceThe Trouble with Being Too Nice

15. MODEL OF BIOBEHAVIORAL
COPING ADAPTIVENESS
Tim e
Reactivity
Normal
Homeostasis
Maladaptive 3
Maladaptive 1
Maladaptive 2:
(e.g., perseverative
thinking, rumination)
Stimulus
Temoshok, Annals NY Acad Sci 2000; 917: 446-455.

16. Analogies: A HypothesisAnalogies: A Hypothesis
Recognize problemRecognize problem
 Functional: identifyFunctional: identify
problem correctlyproblem correctly
 Dysfunctional:Dysfunctional:
denial/exaggeratedenial/exaggerate
Coping/ OutcomeCoping/ Outcome
 Functional: conflictFunctional: conflict
resolution, rebalanceresolution, rebalance
 Dysfunctional: noDysfunctional: no
resolution, chronicresolution, chronic
stress/ panic, PTSDstress/ panic, PTSD
Recognize antigenRecognize antigen
 Functional: recognizeFunctional: recognize
pathogen correctlypathogen correctly
 Dysfunctional:Dysfunctional: SignalSignal
impairmentimpairment
Coping/OutcomeCoping/Outcome
 Functional: neutralizeFunctional: neutralize
pathogen/ wound healingpathogen/ wound healing
 Dysfunctional: immuneDysfunctional: immune
incompetence, cancer/incompetence, cancer/
auto-immune disordersauto-immune disorders
Central Nervous System Immune System

17. 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 andThe 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, andSuccessful or adaptive coping reduces stress, and
determines whether internal and external stimuli aredetermines 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 arePersistent trait-like Individual differences in coping are
termed coping styles/ patterns/ proclivities in thetermed coping styles/ patterns/ proclivities in the
psychosocial domain, and response patterns in thepsychosocial domain, and response patterns in the
physiological realm.physiological realm.

18. COPING STYLE
Type A
Adaptiveness
Type C
Type B
High
Low
Temoshok, et al. Journal of Psychosomatic Research 1985; 29: 139-153.

19. HYPOTHETICAL MODEL: DYSREGULATEDEMOTIONS ARE
ASSOCIATEDWITHDYSREGULATEDBIOLOGICAL
PROCESSES ANDNEGATIVE HEALTHOUTCOMES
Re co g nitio n and Expre ssio n
o f Ne g ative Em o tio ns
EffectsonHealth
Type C Type A
Positive
Negative
Type D
Type B
“resilient”
Under-response to
stress/pathogen
Over-response
to stress/pathogen
Cardiovascular DiseaseImmune -mediated
disorders
repression suppression Over-expression
Appropriate
expression

20. 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 andThe 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 aThis maladaptive coping pattern keeps the individual in a
chronic state of stress with concomitant dysregulation ofchronic state of stress with concomitant dysregulation of
homeostatic responses, includinghomeostatic responses, including inappropriateinappropriate responses toresponses to
stressors, i.e., increased physiological reactivity, andstressors, i.e., increased physiological reactivity, and
decreased recoverydecreased recovery (Temoshok,(Temoshok, Ann NY Acad SciAnn NY Acad Sci 2000).2000).

21. LACK OF SYNCHRONY BETWEEN PHYSIOLOGY
AND PSYCHOLOGY IN HIGH TYPE C INDIVIDUALS
Physiological
Response
Psychological response
StressorTime
Kneier & Temoshok, J Psychosom Res 1984

24. Type C and Prognostic IndicatorsType 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 withStronger Type C coping is associated with
significantly lower number of lymphocytes atsignificantly lower number of lymphocytes at
primary tumor site (positive prog. indicator).primary tumor site (positive prog. indicator).
 Stronger Type C coping associated withStronger Type C coping associated with
significantly higher mitotic rate of the cancersignificantly higher mitotic rate of the cancer
(negative prognostic indicator).(negative prognostic indicator).
 Cf. current studies pioneered by SusanCf. current studies pioneered by Susan
Lutgendorf on tumor microenvironment.Lutgendorf on tumor microenvironment.

25. Individual Differences and HIVIndividual Differences and HIV
 The considerable variability in HIV diseaseThe considerable variability in HIV disease
progression cannot be accounted for entirely byprogression cannot be accounted for entirely by
treatment, adherence, or genotype, and may betreatment, 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 havePNI researchers over the past 20 years have
suggested several individual difference factors thatsuggested several individual difference factors that
may contribute to faster or slower HIV progressionmay contribute to faster or slower HIV progression
or non-progression.or non-progression.
 Individual difference factors may explain why someIndividual 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.

26. Early Study:Early Study:
HR Response & AIDS SurvivalHR Response & AIDS Survival
In 28 patients with AIDS,In 28 patients with AIDS,
heart rate response (toheart rate response (to
describing 5 emotionaldescribing 5 emotional
situations over the pastsituations over the past
week) which betterweek) which better
approximated the inverted-Uapproximated the inverted-U
shaped curve of normalshaped curve of normal
homeostasis significantlyhomeostasis significantly
predicted months survival.*predicted months survival.*
The other 3 hypotheticallyThe other 3 hypothetically
maladaptive patterns hadmaladaptive patterns had
significantly shortersignificantly shorter
survival.survival.
Temoshok et al. 1987.Temoshok et al. 1987.

27. 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.

28. Elucidating Biopsychosocial MediatorsElucidating 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. 2009Temoshok 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

29. Longitudinal Study OverviewLongitudinal Study Overview
■■ 5+ year NIH R01 study5+ year NIH R01 study to identify the complexto identify the complex
mechanisms by which coping and interrelatedmechanisms by which coping and interrelated
psychosocial variables may interact withpsychosocial variables may interact with
immunological factors and physiological responseimmunological factors and physiological response
patterns to affect HIV progression.patterns to affect HIV progression.
■■ 200 HIV+ participants (49% men, 92% African200 HIV+ participants (49% men, 92% African
American in HIV primary care clinic in inner cityAmerican in HIV primary care clinic in inner city
Baltimore.Baltimore.
■■ 69% currently prescribed ART69% currently prescribed ART
■■ 25% on cardiovascular medications, primarily for25% on cardiovascular medications, primarily for
high blood pressurehigh blood pressure
■■ 34% on psychiatric medications, primarily34% on psychiatric medications, primarily
antidepressantsantidepressants
■■ 17% on methadone maintenance17% on methadone maintenance

30. Laboratory MethodsLaboratory Methods
 A number of studies suggest that stress can enhanceA number of studies suggest that stress can enhance
production of proinflammatory cytokines, notablyproduction of proinflammatory cytokines, notably interleukin-6.interleukin-6.
 Dysregulation of the pro- and anti-inflammatory balance hasDysregulation 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 onePeripheral blood samples were drawn approximately one
week before the psychophysiology tasks.week before the psychophysiology tasks.
 In vitroIn vitro production of IL-6, MIP-1α, and MIP-1βproduction of IL-6, MIP-1α, and MIP-1β was measuredwas measured
in response to three antigens: Candida, PHA, and p24 (HIVin response to three antigens: Candida, PHA, and p24 (HIV
core protein).core protein).
 Assays for MIP-1α and MIP-1β performed by ELISA.Assays for MIP-1α and MIP-1β performed by ELISA.
 Stimulation Index (SI): Antigen-induced chemokine productionStimulation Index (SI): Antigen-induced chemokine production
compared to unstimulated background controls.compared to unstimulated background controls.

31. Psychosocial Measures: AlexithymiaPsychosocial Measures: Alexithymia
 A personality construct that denotes a deficit in the cognitiveA 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 physiologicalDifficulty distinguishing emotions and physiological
sensations.sensations.
 Unlike Type C in reporting an undifferentiated, diffuseUnlike Type C in reporting an undifferentiated, diffuse
psychological distress, which fosters a hypervigilance towardpsychological distress, which fosters a hypervigilance toward
somatic sensations and increased report of somaticsomatic 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 ofBelieved to be a predisposing factor for the development of
medically unexplained symptoms and somatoform disorders.medically unexplained symptoms and somatoform disorders.

32. Psychophysiology MethodsPsychophysiology Methods
 Participants complete two emotion-inductionParticipants complete two emotion-induction
tasks approximately one week after each bloodtasks approximately one week after each blood
draw.draw.
 Each 3-minute task is preceded by a 5-minuteEach 3-minute task is preceded by a 5-minute
resting baseline and followed by a 5-minuteresting baseline and followed by a 5-minute
resting recovery period.resting recovery period.
 Heart rate and blood pressure are monitored atHeart rate and blood pressure are monitored at
90-second intervals.90-second intervals.
 Variables of interest include reactivity during theVariables of interest include reactivity during the
test period and return to baseline during thetest period and return to baseline during the
recovery period.recovery period.

33. Baseline regression analyses of Type C andBaseline regression analyses of Type C and
alexithymia to MIP-1alexithymia to MIP-1α and IL-6 productionα and IL-6 production
TemoshokTemoshok et al. Brain Behavior & Immunityet al. Brain Behavior & Immunity 20082008
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

34. Linear regression analyses of alexithymia andLinear regression analyses of alexithymia and
heart rate variables to p24 MIP-1heart rate variables to p24 MIP-1αα productionproduction
TemoshokTemoshok et al. Brain Behavior Immunityet al. Brain Behavior Immunity 20082008
After adjustment for age,After adjustment for age,
CD4+ count,CD4+ count,
cardiovascularcardiovascular
medications, andmedications, and
methadone use, highermethadone use, higher
alexithymia, greater HRalexithymia, greater HR
reactivity, and poorer HRreactivity, and poorer HR
recovery (collapsedrecovery (collapsed
across tasks) wereacross tasks) were
associated with lessassociated with less MIP-MIP-
11αα production to the p24production to the p24
antigen.antigen.
Predictors Dependent Variable:
MIP-1α to p24
Standardized
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

35. Baseline Blood Pressure Reactivity PredictsBaseline Blood Pressure Reactivity Predicts
Stimulated MIP-1Stimulated MIP-1ββ Production at 24 MonthsProduction at 24 Months
After adjustment forAfter adjustment for
age, CD4 count atage, CD4 count at
baseline,baseline,
cardiovascularcardiovascular
medications, andmedications, and
methadone use,methadone use,
greater SBP and DBPgreater SBP and DBP
reactivity during thereactivity during the
Anger Recall Task atAnger Recall Task at
baseline predictedbaseline predicted
reduced p24reduced p24
stimulated MIP-1stimulated MIP-1ββ
production at 24production 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

36. Baseline Blood Pressure Recovery PredictsBaseline Blood Pressure Recovery Predicts
Stimulated MIP-1Stimulated MIP-1ββ Production at 24 MonthsProduction at 24 Months
After adjustment for age,After adjustment for age,
CD4 count at baseline,CD4 count at baseline,
cardiovascularcardiovascular
medications, andmedications, and
methadone use, highermethadone use, higher
SBP and DBP during theSBP and DBP during the
recovery period (i.e.,recovery period (i.e.,
poorer recovery)poorer recovery)
following the Angerfollowing the Anger
Recall Task at baseline,Recall Task at baseline,
predicted reduced p24predicted 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

37. 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

38. 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

39. SummarySummary
 Baseline findingsBaseline findings: Stress sustained as a result of: Stress sustained as a result of emotionalemotional
and autonomic dysregulationand autonomic dysregulation (alexithymia, Type C coping,(alexithymia, Type C coping,
overreactivity) was associated withoverreactivity) was associated with immune dysregulationimmune dysregulation,,
characterized by enhanced immune activating IL-6 productioncharacterized 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-HIVpathways), 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 allresults, Type C coping predicted more IL-6 production at all
(12, 18, 24, 36, and 48-month follow-up points(12, 18, 24, 36, and 48-month follow-up points).).
 A chronic pattern of physiological dysregulation, synergisticA chronic pattern of physiological dysregulation, synergistic
with emotional dysregulation, predicted persistent suppressionwith emotional dysregulation, predicted persistent suppression
of anti-HIVof anti-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

40. 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 slopeHomeostasis: 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 stressorImmune activation to a psychological stressor
is not appropriate!is not appropriate!
 Another example: the inappropriatelyAnother example: the inappropriately
activated (“promiscuous”) but ineffectiveactivated (“promiscuous”) but ineffective
response of the immune system to early HIVresponse of the immune system to early HIV
infection, and immune over-activation.infection, and immune over-activation.

41. Longitudinal Study ConclusionsLongitudinal Study Conclusions
■■ ResultsResults suggest that dysregulated HIV-specificsuggest that dysregulated HIV-specific
cytokine (IL-6) production is associated withcytokine (IL-6) production is associated with
Type C coping and may contribute toType C coping and may contribute to
mechanisms mediating previously documentedmechanisms mediating previously documented
negative effects on HIV progression.negative effects on HIV progression.
 Biopsychosocial interventionsBiopsychosocial interventions to change Type Cto change Type C
coping and to promote regulated physiology andcoping and to promote regulated physiology and
immune function may also contribute to slowingimmune function may also contribute to slowing
HIV progression.HIV progression.

42. RecommendationsRecommendations
 Much PNI research has documented links betweenMuch 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 notBut to the extent high Type C copers do not
recognize and/or do not acknowledge theirrecognize and/or do not acknowledge their
underlying depression, they are unlikely to seek orunderlying 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 identifyTherefore, we need innovative methods to identify
Type C copers, and innovative biopsychosocialType C copers, and innovative biopsychosocial
interventions to help them change dysfunctionalinterventions to help them change dysfunctional
Type C coping and its underlying depression.Type C coping and its underlying depression.

43. Can we ameliorate maladaptive coping to positivelyCan 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 influencepsychosocial interventions intended to influence
more salutary HIV medical outcomes.more salutary HIV medical outcomes.
 Test these interventions for their ability toTest 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
dysregulationdysregulation
which, hypothetically, will also decrease immunewhich, hypothetically, will also decrease immune
dysregulation, particularly inappropriatedysregulation, particularly inappropriate
activation and inflammatory responses.activation and inflammatory responses.