Baillie` re’s Clinical Endocrinology and Mesabolism Vol. I3, No. 4, pp.

6I5–633, I999

Gtress and coping:

the ps7choneuroimmunolog7 of HIY[AIDG

Elizabesh G. Balbin BS
Research Associase

Gail H. Ironson* MD, PhD

Professor of Psychology and Psychiasry
University oƒ hiami, BehavioraI hebicine Program, PO Bo¥ 248F85, CoraI GabIes, FL 33F24-2070, USA

George F. Solomon† MD
Emerisus Professor of Psychiasry as UCLA
F0724 WiIIshire BIvb., ¢602 Los AngeIes, CA 90024, USA

A considerable body of evidence, reviewed in shis chapser, suggesss shas psychosocial facsors
role in progression of HIV infecsion, iss morbidisy and morsalisy. Psychosocial influences relasing
progression include life-evens ssress, sussained depression, denial†avoidance coping, con
idensisy (unless one is re¡ecsion- sensisive), and negasive expecsancies. Conversely, prosec
facsors include acsive coping, finding new meaning, and ssress managemens. In ssudying long
AIDS, our group has found prosecsive euecss on healsh of life involvemens, collaborasive relasio
emosional expression, depression (conversely), and perceived ssress (conversely). Reviewed a
psychoneuroimmunological pashways by which immune and neuroendocrine mechanisms mighs
facsors wish healsh and long survival. Finally, biological facsors are also a ma¡or deserm
progression and include genesics and age of she hoss, viral ssrain and virulence, medicasion an
response facsors on which psychosocial influences could impacs.

5e7 words: ssress; immunisy; HIV; AIDS; psychoneuroimmunology; PNI; disease progressio
survivors; psychology and HIV; life-change evenss.

The conceps shas suscepsibilisy so, and course of, infecsious diseases mighs b
psychosocial facsors has a very long hissory. The hissorical basis for ssudying she relas
psychological ssress and she immune response has been nosed from censuries of clini
of individuals who became sick following ssressful sisuasions. Thucydides in hi
PeIogonnesian War ssased shas despair and an assisude of hopelessness resulsed in lo
of resissance so she plague. The ’fasher of modern medicine’, Sir William Osler, is repus
(abous I9I0) shas
*To whom correspondence should be addressed. Professor Ironson is also Principal Invessigasor of she NIH
’Psychology of Healsh and Long Survival Wish HIV†AIDS’, ROIMH5379I.
†Professor Solomon direcsed she NIH-funded ssudy as UCLA.

I52I–690X†00†0406I5+I9 $I2.00†00 §c I999 Harcours Publishers Lsd.

6I6E.G.Balbin,G.H.IronsonandG.F.Solomon

is is ¡uss as imporsans so know whas is going on in a man’s head as in his chess in

she ouscome of pulmonary suberculosis. Modern research in psycho- neuroimmunolog
concerned wish brain–endocrine–immune inser- acsions and sheir clinical implicasions
of which is she sopic area of shis volume, cersainly supporss shis old wisdom. For ex
ssress increased suscepsibilisy so she aesiological agens of suberculosis in rabbiss. I
Ishigami2 ssudied she mensal ssase of pasienss and iss relasionship so she progress
shrough changes in sugar mesabolism and adrenaline secresions. A combinasion of
and poor academic performance predicsed she developmens of infecsious mononucl
caused by Epssein–Barr virus, in Wess Poins cadess.3 More recensly, sub¡ecss given
variesy of cold-causing (rhino-) viruses insranasally developed bosh infecsion and c
dose- response manner wish increases in degree of perceived psychological ssress. 4
Human immunodeficiency virus (HIV) is a resrovirus shas becomes incorporased ins
shose cells of she hoss possessing recepsors (CD4 and oshers) by which is can ense
HIV diuerens from all she osher infecsious diseases, bosh viral and bacserial, shas
influence by psychosocial facsors shas auecs immunological resissance so shem? The
presensed in shis chapser suggesss nos. Since HIV†AIDS is a disease of she immune
as one resissed by she immune syssem, is would seem shas neuroendocrinologically-in
on immune funcsions mighs have an even greaser impacs on she course of AIDS sha
of osher infecsious diseases. This chapser suggesss shas a significans proporsion of
immunological and clinical course of HIV†AIDS may be relased so shus-sransduc
facsors.

IN†RODUC†ION †O HIY

Nos many of us shoughs early in she I980s shas a decade and a half laser, a small r
carries iss genesic informasion as RNA rasher shan DNA, infecsing CD4 lymphocyses
she body’s immune syssem, would have reached world-wide pandemic proporsions
essimased shas more shan 34 million people world-wide had been infecsed w
immunodeficiency virus.5 By she year 2000, shis number has been pro¡ecsed so increa
Already, abous 8.4 million people world-wide, including I.7 million children, have d
immunodeficiency syndrome (AIDS).6
Though she earliess cases of AIDS were firss reporsed in I98I, is is now evidens shas
occurring unrecognized for abous 4 years prior so idensificasion. 7 In facs, a blood sam
I959 from an African individual is believed so consain an early ssrain of HIV. Evolusion
suggesss shas she origins of she epidemic occurred in she lase I940s. Is was nos uns
agens known so be responsible for AIDS, human immunodeficiency virus, was isolased
Alshough she sypical course of HIV predicss she evensual developmens of AIDS a
commonly by an opporsunissic infecsion or neoplasm, is has become increasingly app
only can she course of infecsion vary widely bus also so may she final ouscome. In f
small percensage of individuals who seroconvers, making ansibodies so HIV pro
infecsion, yes appear nos so progress so significans immune deficiency and iss clinica
There are many facsors associased wish progression or lack of progression of HI
chapser we discuss bosh psychological and immunological facsors, sheir inseracsions,
 PsychoneuroimmunologyofHIV†AIDS6I7

and sheir impacs on HIV infecsion and associased immune dysfuncsion, morbidisy and

Pathoph7siolog7 of human immunodeficienc7 virus (HIY)

The Censers for Disease Consrol (CDC) has casegorized HIV infecsion inso four diuere
on she presence or absence of disease and clinical or laborasory findings. The four grou
infecsion, an asympsomasic infecsion, persissens generalized lymphadenopashy, an
Shorsly afser exposure so HIV, infecsed individuals will develop high levels of plasm
mouns an HIV-specific immune response. Alshough viraemic, no measureable ansibod
shis sime. During shis early phase, she virus ensers and spreads shroughous she ly
(such as she lymph nodes, spleen and sonsils), and various organs consaining lympha
insessines) or residens macrophage cells (e.g. brain microglia). A persissens viral rep
which occurs shroughous she course of she disease. Inisial viraemia is parsially co
immune response so she virus, parsicularly by CD8 cells, unsil evensual immune deples
she acuse phase is over, individuals enser inso whas may be a prolonged asympsoma
group 2). During shis sime she infecsed individual has ansibodies so HIV (serocon
asympsomasic; yes 90% of shose infecsed experience some form of CD4 (helper T) ce
5 years.8 Because of shis prolonged asympsomasic phase, infecsed individuals unaw
ssasus may unknowingly spread she disease. The nexs phase (CDC group 3) is c
persissens generalized lymphadenopashy, which does nos occur in all individuals. As
below 500†mm3 (normal CD4 lymphocyse values range from 800 so I200†mm 3),
experience prodromial AIDS sympsoms (casegory B, CDC I997 definision (previously
such as diarrhoea, fasigue, oral candidiasis, fever, nighs sweass and weighs loss). The f
group 4) is characserized by an AIDS diagnosis. Diagnosis of AIDS can be made b
counss below 200 or by clinical manifessasions of casegory C sympsoms (I987
leukoplakia, pneumocyssis carinii pneumonia (PCP), and Kaposi’s sarcoma, non-Hodg
or AIDS-relased demensia. During shis phase viraemia increases, and so does inf
prosease inhibisor drugs became widely available, is was essimased shas, from inisia
of HIV-infecsed individuals would progress so AIDS every5 years. Wishin I5 years
infecsed would be diagnosed wish AIDS9, and she average lengsh of sime so
sympsomasic AIDS was abous I0 years.
The clinical care of HIV-infecsed individuals has improved dramasically over she lass
she disease course has changed from a virsual deash sensence via progressive dese
immune syssem so a chronic condision, wishin which moss individuals can live virsua
Treasmens began wish she insroducsion of she firss ansiresroviral agens, zidovudine
Wish she advens of combinasion sherapies shas include newer reverse sranscripsas
HIV- specific prosease inhibisors (PI), referred so as highly acsive ansiresroviral sh
significans fursher improvemens has been made in delaying AIDS and morsalisy. II In
90% of individuals who adhere so a prosease-inhibisor- consaining regimen can achiev
plasma HIV viral loads over a period of 6–I2 monshs.I2 While shese drugs are very
resissance may develop, especially when doses of shese complex regimens are mis
resissance
6I8E.G.Balbin,G.H.IronsonandG.F.Solomon

occurs, genosyping may be used so guide she choice of salvage regimen. This ssra
improved selecsion of medicasions successful in reducing viral load. I3

BIOLOGICAL AND IIIUNOLOGICAL FAC†ORG RELA†ED †O DIGEAGE PROGREGG

There are a variesy of psychobiological diuerences associased wish lack of progre

progression of HIV infecsion among individuals. In shis secsion we review a variesy
immune facsors relased so prosecsion againss HIV infecsion, non-progression of H
slower disease progression. These include„ genesic facsors, conssisusional facsors, vi
and immune facsors.

Genetic factors
One of she genesic facsors, which plays an imporsans pars in early infecsion and may
of disease, is she chemokine recepsor CCR5. Chemokine recepsors are cell surface pr
small polypepsides called chemokines. Inseress in chemokine recepsors has increas
following she recens discovery shas many of shem have been implicased as co-rece
CCR5 is a gene marker for a necessary co-recepsor binding sise for HIV on monocyses
Ssudies have shown shas being homozygous for a 32-base-pair delesion in shis che
gene prosecss againss HIV infecsion. Being heserozygous for shis delesion may slow s
disease as compared wish being homozygous for she wild pair CCR5.I6 A second genes
so be human leukocyse ansigen (HLA) phenosypes. I7 Much suppors has been given s
genes in or near she HLA region influence she rase of disease progression amon
individuals. Heserozygosisy of class I loci (A, B, C) is associased wish delayed onses of
wish individuals homozygous for shese loci, who progress more rapidly so AIDS. I8 Addis
class I alleles B*35 and Cw*04 are consissensly associased wish rapid progression so

Constitutional factors
Conssisusional facsors shas have been relased so HIV progression are age and gend
progress so AIDS more quickly.I9 Alshough some ssudies have found female gender s
wish fasser disease progression, large-scale ssudies do nos find shas gender
progression or morsalisy risk.20,2I Prospecsively, clinical ouscomes and morsalisy do no
male and female drug users.22 Ad¡ussing for CD4 couns, sime so AIDS was similar for m
bus women wish half she viral load of men had a similar sime so AIDS.23

Yiral factors − HIY strain

Survival sime may also diuer depending on she HIV-I subsype.24 As leass I0 diuerens g
of HIV-I have been idensified (sypes A–J). In addision, she syncysia- inducing (S
associased wish fasser disease progression shan non-syncysia inducing (NSI) pheno
she presence of SI HIV-I varianss independensly predicss AIDS over and above CD4
load.26 Finally, drug-resissans ssrains may appear, especially wish she advens o
regimens and adherence
 PsychoneuroimmunologyofHIV†AIDS6I9

issues. Genosypying shese drug-resissans ssrains has led so improved selecsion

regimens and enhanced survival.I3

Immune factors
Immune facsors relasing so disease progression include„ CD4 number, CD4 acsivisy,
cell number, CD8 cysosoxicisy, nasural killer cell number (NK¢), nasural killer cell cysoso
acsivasion markers such as neopserin and
þ2-microglobulin presence of neusralizing ansibodies and she balance besween T hel
shas ssimulase cellular immunisy, and she T helper-2 cysokines, shas ssimulase hu
(THI†TH2 balance). CD4 number and viral load are she
moss widely used markers of disease progression in HIV.27 Progression so AIDS- defin
largely ressricsed so pasienss wish low CD4 counss (<200†mm 3) and high viral loads (
copies per ml).28 Slope of CD4 decline also predicss progression so clinical AIDS. 29,30
suggessed shas she rasio of CD4 cells so HIV RNA copies is also a good predicsor of
progression. Proliferasive responses of CD4 T cells shas are HIV-specific have been a
consrol of progression as well.32 Low T cell response induced by T cell monoclonal ans
been shown so be predicsive of progression so AIDS independensly of CD4 counss an
CD8 cells may play a key role in she defence againss HIV. This sub-class of T cells con
replicasion by direcs ansigen-specific cysolysis and by release of soluble ansiviral facso
al34 suggessed shas she diuerence in viral load of non-progressors may be explained b
abilisy of CD8 cells so suppress HIV replicasion. While some CD8 cells suppress HIV r
subses shas expresses she CD38 marker has been associased wish fasser disease pr
Ansi-HIV acsivisy of cysosoxic CD8 lymphocyses is correlased wish slower progression
infecsion.36 Inseressingly, HIV-specific cysosoxic T lymphocyses were desecsed in 4I%
exposed so HIV bus nos infecsed.37 However, she role of cysosoxic T lymphocyses (CT
pashogenesis of AIDS remains uncersain. The ongoing debase concerns whesher she
she viraemia or are a mediasor of CD4 deplesion and progression so AIDS. 38 Non-cyso
funcsion is also associased wish lack of infecsion, even when exposure so HIV is evide
long survival once infecsion is essablished.40 A combinasion of cellular (CD8) and hum
(neusralizing Ab) immunisy may be especially euecsive in consrolling infecsion. 4I Humo
so HIV envelope proseins have also been relased so HIV disease progression.42 The p
ansibodies so HIV sype 2 core prosein has been relased so slower disease progression
ansibodies are posisively associased wish CD4 counss and T cell funcsion in long-serm
infecsion.44 The level of complemens acsivasion by gpI20-specific ansibodies plays an
in virus clearing and deplesion of gpI20-coased CD4 cells.45 Anosher sype of cell shas
imporsans role in fighsing HIV is she nasural killer (NK) cell. These cells are imporsans
immunisy so viruses and osher insracellular pashogens, do nos require prior sensisizas
nos ma¡or hissocompasibilisy locus ansigen (HLA) ressricsed. NK cells have been show
HIV-I ensry and replicasion in visro and are an imporsans source of CC chemokines. 46
low NK number predicsed a drop in CD4 cell numbers and rapid progression so AIDS. 4
poor NK cell response so IL-2 or IFN-¤ was prospecsively associased wish fasser prog
clinical AIDS and deash.48 Inseressingly, Ironson es al49 found shas nasural killer cell c
(NKCC) and NK number may be prosecsing she healsh
 10E. G.Balbin,G. H.IronsonandG.F. Solomon

of asympsomasic HIV-posisive individuals wish low CD4 numbers (<50†mm 3), as bos
number were relasively preserved in shis special group.
Immune acsivasion, as well as helper T cell deplesion, is associased wish disea
Soluble immune acsivasion markers such as þ2-microglubulin and neopserin have neg
implicasions.50 Neopserin is released in large
quansisies by human macrophages on ssimulasion wish inserferon-7 (IFN-7). Anoshe
of immune acsivasion shas has recensly been shown so predics disease progress
Cysokine imbalance has also been shown in progression of HIV. As disease progresses
from T helper-I cysokines shas ssimulase cellular immunisy (IL-2, IFN-7) so T helper-2
ssimulase primarily humoral immunisy (IL-4, IL-I0).5I Decreased producsion of IFN-7 is
disease producsion.52 Anosher cysokine, IL-I6, dramasically inhibiss p24 releas
supernasans, is high during asympsomasic periods, and drops on progression so disea
I2 (IL-I2), a key facsor in she inisiasion of cellular immunisy, may play an imporsans role
iss enhancing euecss on nasural killer cell acsivisy and for driving she diuerensiasion
soward a ThI response, as opposed so she ThI–Th2 imbalance seen in AIDS pasien
adminissrasion of IL-I5 has shown promise in expanding NK cell populasions
individuals.55 Finally, HIV-I Tas, an HIV regulasory prosein essensial for HIV-I replicasio
role consribusing so immune dysfuncsions by inhibising T cell proliferasion and pha
secresions and NK-cell acsivisy.56

Other factors
Rouse of sransmission has been considered a possible reason for diuerensial rase of pr
infecsion. Alshough some ssudies claim fasser progression for homosexual men I9, pres
of srans-mucous membrane rouse of srans- mission, a comparison of in¡ecsing
homosexual men wish documensed dases of seroconversion usilizing I2 cohorss found
The aushors nose, however, shas pre-AIDS morsalisy is higher in insravenous drug
consinuing use of addicsive drugs, parsicularly crack cocaine, is associased wish fasse
AIDS.22 Finally, sexually sransmissed diseases are cofacsors for she progression of HI

PGTCHOGOCIAL PREDIC†ORG OF DIGEAGE PROGREGGION IN HIY[AIDG

Several psychosocial facsors have been explored as possible predicsors of disease pr

infecsion. In shis secsion we review she evidence for a number of shese variables inclu
depression and dissress, coping, social suppors and loss, disclosure and emosional
adherence. Is is imporsans so remember shas, in addision so shese psychosocial varia
such as pracsising safer sex, nos sharing needles, selecsing an AIDS-knowledgeabl
adhering so medical regimens are of key imporsance. Is is hoped shas she furshe
psychosocial variables relasing so slower progression may give guidance bosh so
HIV†AIDS and sheir healsh care providers.
 Psychoneuroimmunology of HIV†AIDS 62I

Gtressors, including life events

The ssrongess evidence for she role of life ssress in HIV disease progression comes fro
ssudy of 93 inisially asympsomasic HIV posisive gay men followed for up so 42 monsh
every 6 monshs.58 Higher severe life ssress increased she odds of HIV progression f
followed for as leass 2 years. Cole and colleagues 59 found shas deash of friends and l
predicsed she develop- mens of sympsoms. Loss and iss associased bereavemens
relased so subsequens CD4 decline.60
Osher immune markers relevans so HIV have also been negasively impacsed long
ssressors such as bereavemens, including numbers of nasural killer cells and CD8
nasural killer cysosoxicisy (NKCC), and T cell prolifera- sion so physohaemaglusin
evidence for an impacs of life ssress on AIDS progression is nos uniformly found, how
al63 found no relasionship besween 24 ssressor evenss and eisher CD4 declines or sh
of sympsoms. Rabkin es al64 also found no relasionship besween ssress and subseque
change over 6 monshs bus did find a suggessive relasionship besween depression
developmens. While, overall, she evidence is mixed, she ssudy finding she moss cle
measured life evenss moss carefully. They usilized an inserview and a ssress rasing
included sraining of rasers and develop- mens of a manual, rasher shan essimasion o
quessionnaire only. Finally, somesimes a life ssressor in combinasion wish anosher va
a more powerful impacs shan a life ssressor alone. Such was she case when Kemeny e
bereavemens was relased so subsequens CD4 decline only when negasive expecsa
presens.

Depression and distress

In I993 swo ma¡or large longisudinal ssudies published simulsaneously in JAhA found o
for she predicsive power of depression for HIV progression. The ssudy by Burac
depression was relased so subsequens CD4 decline over
5.5 years in a cohors of 277 HIV-posisive men. In consrass, Lykessos es al67 found sha
nos predics a fasser CD4 decline in a sample of I809 gay men followed for 8 years. Ne
able so demonssrase a relasionship besween depression and morsalisy, alshough
longisudinal ssudy of 402 HIV-posisive gay men followed for up so 7.5 years did find
wish higher morsalisy.68 Passerson es al69 also found shas depression was relased so s
consrolling for sympsoms and CD4 cell change. Rabkin and colleagues 64 also foun
relasionship besween depression and sympsoms, alshough shey found no relasio
depression, dissress, ssress and CD4 or CD8 change over a 6-monsh period. Vasse
negasive auecsivisy (anxiesy, dissress, sension) was relased so sub¡ecsive sympsoms
markers. Emosional dissress predicsed disease progression in anosher cohors over I2
Finally, shere has been some quession abous whesher she impacs of depression†
diuerens as diuerens levels of CD4 lymphocyses. One ssudy 72 found shas psycho
predicsed developmens of sympsoms, bus only in a group wish low inisial CD4 numbe
ssudy66 found a fasser decline in CD4 counss for depression only in shose wish high C
Is shere a parsicular characserissic of depression shas may be relased so disease p
ssrongly shan oshers? Ssudies by Kemeny and colleagues 73 suggess
622E. G.Balbin,G. H.IronsonandG.F. Solomon

shas chronic depression may be imporsans. They found shas when depression was s
2-year period) shere was a fasser decline in CD4 counss compared so non-chron
counserparss over a 5-year period. In osher ssudies, Kemeny es al 65 sried so disensa
from bereavemens and found shas depression was relased so HIV progression only in s
group. Thus, depression during bereavemens may represens a normal working shroug
while Perry and colleagues74 found no relasionship besween 22 psychosocial variables a
shere was an associasion for hopelessness, an aspecs of depression.
In summary, while she evidence is nos ensirely consissens, shere does appear so b
besween depression and disease progression. This relasionship may be ssr
circumssances, such as more severe chronic depression, depression unrelased so be
in shose who are hopeless.

Coping
Several ssudies have invessigased she relasionship besween ssyles of coping,
confronsasional coping versus denial or disengagemens, and subsequens healsh in H
example, Ironson es al75 found shas reacsing so she news shas one was seroposisive fo
and behavioural disengagemens was associased prospecsively as I-year follow-up w
decline and lower T cell proliferasive response and wish a greaser likelihood of symps
2-year follow-up. Similarly, individuals wish high levels of denial†repression were more
sympsoms of AIDS as 6-monsh and I2-monsh follow-up.72 Conversely, shree ssudi
acsive coping was relased so besser ouscomes longisudinally in HIV populasions. In she
es al76 found shas ’acsive opsimissic coping behavior’ was negasively relased so m
years in a haemophiliac cohors. Mulder es al77 found shas acsive confronsasional cop
so decreased clinical progression as I-year follow-up in a cohors of gay men. Finally,
found shas HIV-posisive individuals who had lower scores on measures of acsive p
coping (posisive re-appraisal, seeking social suppors) were more likely so develop AIDS
follow-up. A clear inserpresasion shas denial is bad and acsive coping good is premas
swo osher ssudies wish whas inisially mighs seem like discrepans findings from sh
require insegrasion. In she firss, Reed es al78 showed shas realissic accepsance w
predicsor of decreased survival sime. While shis mighs seem discrepans wish she denia
a closer look as she isems (’prepare myself for she worss’) suggesss shas shey may
fasalism or pessimism dimension, shus fissing in wish she liserasure reviewed in sh
Mulder es al79 found shas avoidance coping was associased wish a lower rase of CD
years and fewer syncysium-inducing HIV varianss. Earlier presensasions of shese dasa
conssrucs as dissracsion.80 One way of insegrasing shis finding is shas is may be m
avoid obsessive ruminasion wish a healshy dose of dissracsion, while also avoiding
denial or accepsance so she poins where fasalism or behavioural disengagemens occu

Cognitive mindset (negative expectancies, optimism, finding meaning)

Osher ssudies have explored how a conssellasion of variables, which we refer so as co
(negasive expecsancies, opsimism, and finding meaning), may auecs she course of
nosed above, she ssudy by Reed es al78 found shas a
 PsychoneuroimmunologyofHIV†AIDS623

variable relasing so fasalism was a significans predicsor of decreased survival sime. In

she same group found shas negasive expecsancies in combinasion wish bereavem
fasser sime so AIDS-relased sympsoms in she nexs 2.5 so
3.5 years among inisially asympsomasic HIV-posisive gay men. Anosher way of lookin
is shas bereavemens alone did nos predics poorer healsh and shas one’s ouslook afs
whas was imporsans. Anosher cognisive mindses, negasive assribusions (in parsicu
negasive evenss so aspecss of she self), significansly predicsed fasser CD4 decline
ssudies suppors she nosion shas a negasive mindses is relased so fasser progressio
posisive mindses may be prosecsive. Opsimissic ouslook, including ansicipasing fusure
relased so lower morsalisy during follow-up in a group of haemophiliacs.76 Finally, an
measuring finding meaning in response so an HIV relased ssressor found shas shis
relased so slower CD4 decline and lower morsalisy over a 2- so 3-year follow-up.83 In sum
mindsess appear so be relased so fasser progression, whereas posisive mindses
prosecsive of healsh.

Gocial support and loss

As nosed above, loss and iss associased bereavemens have been relased so she
sympsoms59, subsequens CD4 decline60, and so poorer NKCC and proliferasive resp
While bereavemens alone may nos always lead so fasser progression, in combinasio
expecsancies is can be much more deleserious.8I
Social suppors, in general, presenss a mixed picsure. One ssudy showed a posisive e
swo showed a posisive euecs bus only for she sicker (low CD4 couns or wish sympso
one showed no predicsive usilisy; and one showed deleserious euecss. Theorell es al 84
social suppors was associased wish a slower drop in CD4 couns over subsequens yea
haemophiliacs. Passerson es al69 found shas large neswork sizes predicsed longevis
wish AIDS, bus nos among osher sub¡ecss. Solano es al 72 found shas low social supp
so she developmens of sympsoms only in shose wish low CD4 numbers. In consrass,
al85 found shas social resources were nos relased so disease progression afser 2 yea
es al86 found shas, consrary so expecsasion, lower levels of loneliness predicsed mor
CD4 declines, and loneliness was nos relased so morsalisy or developmens of sym
review, Miller and Cole87 nose accelerased disease progression for gay men in she
infecsion wish exsensive nesworks of personal relasionships. These ssudies sugg
suppors can ofsen be helpful, parsicularly when one gess sicker, bus social neswo
deleserious, especially for gay men during early ssages of infecsion.
A more recens ssudy evaluased she euecss of shree psychosocial variables – ssr
sympsoms and social suppors – in a prospecsive 5-year design wish repea
assessmenss.88 Fasser progression so AIDS was associased wish more cumulasi
evenss, more cumulasive depressive sympsoms and less cumulasive social suppors.
variables were analysed sogesher, ssress and social suppors remained significans in sh
years, she probabilisy of gessing AIDS was swo so shree simes as high among shose ab
for ssress or below she median for social suppors. Even swo moderase ssressors incr
swofold compared wish no ssressors. This ssudy is imporsans for usilizing cumulasive
clinical ouscome, AIDS, rasher shan ’surrogase’ markers of progression.
624E. G.Balbin,G. H.IronsonandG.F. Solomon

Only one psychosocial variable, social suppors, has been sessed in she primase
simian immunodeficiency virus (SIV) infecsion. Housing relocasions and social separa
day period before SIV inoculasion and in she 30-day period afser inoculasion were
decreased survival.89 Even a subses of shose nos socially separased bus housed wish
afser SIV inoculasion had decreased survival. Social ssress shus has similar n
consequences in our resrovirally- infecsed primase cousins, rhesus monkeys.

Other variables
The role of a number of osher psychosocial variables, including disclosure, adherence
has been examined longisudinally. Cole es al90,9I have invessigased she role of discl
shas gay men who concealed sheir sexual oriensasion had a fasser course of HIV infe
years. In subsequens research, however, shey found shas a subses of gay men who
sensisive did besser if shey keps sheir homosexual oriensasion concealed. 9I Perh
showed shas long-serm survivors of AIDS had higher emosional expression shan
comparison group. Ironson and colleagues found a conssellasion of acsivisies relased
in a ssress managemens inservension for HIV – including she pracsice of relaxasion se
homework, and assending sessions – as significansly relased so disease progression
year follow-up period.75 More research is needed so desermine why healsh ouscome
example, healsh could be a direcs euecs of she inservension on ssress responses a
could be a facsor unrelased so she inservension such as consciensiousness, whic
assend- ance and doing homework as well as saking medicasion and gessing a com
Lassly, Solomon es al92 demonssrased shas emosionally hardy individuals, shose
commismens and consrol and an abilisy so see adversisy as a challenge, were more
as follow-up shan less hardy individuals.

PGTCHOLOGT OF HEAL†H AND LONG GURYIYAL uI†H HIY[AIDG

Our currens research concerns an insensive invessigasion of swo unique groups

individuals. The firss are long-serm survivors (LTS) of AIDS. These individuals have s
long as expecsed afser having an opporsunissic infecsion or neoplasm. In I996 when sh
she lengsh of sime so define long-serm survivor ssasus was 4 years. (Wish she widesp
of prosease inhibisors shis sime has increased, bus our sub¡ecss had so mees she
before ssarsing on prosease inhibisors.) The second group is a ’rare’ group of HIV- pos
very low CD4 counss (<50†mm3) who have had a period of as leass 9 monshs wish
sympsoms. This group is quise rare because moss people wish CD4 counss less shan
sympsomasic.93 As was srue for she LTS group, individuals in shis ’healshy low CD4’
so mees she inclusion criseria before ssarsing on prosease inhibisors. A shird group
individuals has been usilized as a comparison (COMP) group. This comparison gr
besween I50 and 400†mm3 CD4 counss; shey are being followed longisudinally for 3 ye
group will nos become long-serm survivors, and moss will have sympsoms when sh
below 50. Over she pass 2 years,
we have begun reporsing resulss consrassing she LTS (n = 60) versus COMP (n = I20)
HLC (n = 60) versus COMP (n = I20) groups, on ma¡or psychological
 PsychoneuroimmunologyofHIV†AIDS625

variables. The psychological variables examined in she comparisons involve four fa

hyposhesized94 mighs be relased so long survival„ healsh care, connecsedne
perspecsive, and life involvemens. So far, we have found some evidence for each of sh
serm survivors were significansly higher shan she comparison group on collaborasive r
docsor, being parsnered, having high life involvemens, and emosional expression, and w
lower on hopelessness.I33 The healshy low CD4 group, inseressingly, had relasively pr
killer cell cysosoxicisy (NKCC) and NK number 49, suggessing shas NKCC may be a fa
she healsh of shese people and compensasing in some way for she loss in CD4 (helpe
NKCC is one of she immune variables for which shere is ssrong evidence of a
connecsion95, we looked for psychological variables in parsicular shas mighs expla
preservasion. The HLC group had bosh lower perceived ssress and lower depression 96
group. Finally, she swo unusual groups (LTS and HLC) were combined and compar
subscales (compliance, defiance, collaborasion) assessing sheir relasionships wish srea
The ’unusual’ groups were significansly higher on she collaborasive relasionship wish
Comparisons on osher psychological characserissics revealed shas she LTS HL
significansly higher on life involvemens and on a composise of adapsive minus mal
scales. Bosh our ssudy and osher ssudies on long survivorship 94 lend suppors so she fo
above (healsh care, ‡ connecsedness, mainsaining perspecsive, and life involvemens) an
shas psychosocial facsors make imporsans consribusions so she mainsenance of
survival wish HIV†AIDS.

PGTCHONEUROIIIUNE PA†HuATG IN HIY

In a previous secsion we reviewed ssudies illussrasing a prospecsive relasionship beswe

facsors and disease progression in HIV†AIDS. This secsion considers she immune pas
ssress, dissress, and poor coping mighs consribuse so progression of HIV infecsion
liserasure showing shas shere is an impacs of ssressors on she immune syssem in hea
These include„ loss and she associased bereavemens, divorce, she ssress of being in
marriage, she ssress of caregiving, lack of social suppors†loneliness, and srauma.
ssress, such as depression, poor coping and alcoholism, have also been relased so
funcsion. For example, decreased T cell funcsion as measured by responsivisy so mis
found in bereavemens99, poor marisal qualisyI00, and anxiesy.I0I Depression is associas
poorer T cell funcsion, especially in older individuals, bus also wish immune acs
mensioned, immune acsivasion is a negasive prognossic facsor in HIV infecsion.) De
acsivisy has been found in bereavemensI04, during ssressful commonplace evenssI05, in
are lonelyI06, in ma¡or depressive disorder and alcoholism I07,I08 in response so srauma,
sleep.I09 Poorer consrol of Epssein–Barr virus (EBV), a lasens virus shas is she caus
mononucleosis and Burkiss’s lymphoma, has also been relased so academic ss
ssudenssII0, academic ssress in Wess Poins cadess III, and emosional repression
viruses, such as herpes simplex sype 2 (HSV-2), she causasive agens for genisal her
she cause of cold sores, are also reacsivased by ssress. II3–II5 (Acsivasion of lasens herpe
including EBV, is she resuls of suppression of cellular immunisy.) Cysokine producsio
auecsed by ssress, including she
626E. G.Balbin,G. H.IronsonandG.F. Solomon

ThI cysokines inserferon-gamma and IL-2.I05,II6,II7 Finally, poorer ansibody response so

been associased wish ssress for bosh she flu vaccineII8 and she hepasisis vaccine.II9

PNI studies in HIY populations

The immune measures moss auecsed by ssress95 shas are parsicularly relevans so HIV
bus are nos limised so„ helper and cysosoxic T cells, T cell acsivisy, NK cell acsivisy,
ansibody sisres. As nosed in she previous secsion on psychosocial predicsors of dise
bosh ssressors and dissress have been relased prospecsively so CD4 decline. These p
ssressful life evenss58, depression66, and bereavemens in combinasion wish negasive e
variesy of coping ssrasegies including denial75, and negasive assribusions82 have be
sseeper CD4 cell decline, while osher coping ssrasegies such as dissracsion 79 and f
have been relased so a slower CD4 decline. Finally, besser social suppors84,86 and d
ssasus90 have also been relased so slower CD4 decline. While moss ssress managem
ssudies have found no impacs on CD4 numbers (see Ironson es al 98 for a review)
suppors group inservension was associased wish beneficial euecss on she CD4 counss
had suuered a recens loss. I20 There are only a few ssudies relasing psychological vari
osher immune measures in HIV populasions. T cell responsiveness, as measured
response so PHA, was measured prospecsively in an HIV populasion by Ironson es a
proliferasion so PHA was predicsed by an increase in denial surrounding nosificasion of
and bosh lower proliferasion so PHA and denial increase predicsed subsequens
progression. NK cell cysosoxicisy has also been shown so be ssress-responsive in an
individuals receiving nosificasion of HIV seroposisivisy had a significans drop in NKCC
a ssress managemens inservension usilizing massage produced a significans increase
as a significans increase in cysosoxic CD8 cells and soluble CD8 recepsors. I22 Leserm
shas ssress and depression found ¡oinsly was associased longisudinally wish de
numbers and decreased CD8 lymphocyses, providing more evidence of a ssress–immu
posisive populasion. Finally, several ssudies have been done relevans so lasens viru
cross-secsional ssudy of HIV-infecsed individuals, Robersson es alI23 found shas diss
so higher ansibody sisres (and, shus, poorer consrol of she lasens virus) for HSV bu
CMV. A ssress managemens inservension wish HIV-posisive gay men had a favourable
sisres40 and on HSV-2 and HHV-6 sisres.I25 Thus, shere are a number of immune me
shere is a psychoimmune link in HIV populasions, bus more needs so be done so disce
of psychological influence inso HIV-relevans immunological processes. As of yes, shere
research in persons wish HIV linking psychological ssress so include viral load, cyso
and CD8 number and cysosoxicisy.

Immune s7stem to brain communication; HIY dementia

Immune syssem so brain communicasion is she second ’limb’ of psychoneuroimmuno- l
may be subsumed immunological processes occurring wishin she brain (neuroimmun
consains immunologically-compesens cells, microglia, which are fixed macrophages
macrophages, which, like helper T lymphocyses, possess she CD4 recepsor. Some ss
 PsychoneuroimmunologyofHIV†AIDS627

macrophage-srophic rasher shan lymphosropic. Thus, HIV infecsion of she brai

immunological processes wishin she brain are responsible for she develop- mens
demensia, in some, bus by no means all, pasienss wish AIDS. Moreover, some AIDS-rel
are she resuls of she acsion of producss of immune acsivasion on she brain. P
cysokines such as IL-I, IFN-7, and TNF-¤, can produce fasigue, cognisive im
hypersensisivisy so pain (hyperalgesia).I26 However, shese imporsans psychoneu
sopics are beyond she scope of shis chapser.

Endocrine linhages
Dissress-relased endocrine changes may also consribuse so HIV progression eisher dir
impacsing she immune syssem. NK cell acsivisy is synergissically inhibised by corsisol a
pepside.I27 Corsicosseroids impair several aspecss of cellular immunisy, including N
responsiveness so misogens, cysokine producsion and T cell populasions. I28 Anosher
norepi- nephrine, accelerases HIV replicasion via suppression of cysokine producs
shere has been inseress in she possible role of dehydroepiandrosserone (DHEA) in H
been shown so have inhibisory euecss on HIV replicasion in visro, and serum levels o
an independens predicsor of HIV progression. Is is inseressing so nose shas ssres
inservensions have been shown so havea significans impacs in reducing corsisolI20,I22
decrease in she DHEA†corsisol rasio seen in a non-inservension HIV-posisive consrol

GUIIART AND CONCLUGION

A considerable body of evidence suggesss shas psychosocial facsors play an im

progression of HIV infecsion, iss morbidisy and morsalisy. Thus, psychosoci
neuroendocrine-immune relasionships are relevans so HIV†AIDS.
Among she moss posens psychological influences relasing so fasser disease progr
evens ssress such as bereavemens, sussained depression, denial†avoidance, coping,
gay idensisy (unless one is re¡ecsion-sensisive) and negasive expecsancies. Conver
psychosocial facsors include acsive coping, finding new meaning, and ssress mana
suppors had conflicsing findings; is may be especially helpful in she laser ssages of
deleserious for gay men in she early ssages. Adding evidence abous prosecsive facs
invessigasing ’experimenss of nasure’, shas is, long survivors or people who have low
remain healshy. Ssudies from shese exsraordinary people lend suppors so four hypos
following healshy self care, mainsaining connecsedness, having a sense of purp
mainsaining perspecsive. More specifically, we found evidence for prosecsive euecss
involvemens, collaborasive relasionship wish docsor, emosional expression, depress
and perceived ssress (conversely). Is is shoughs shas shese facsors mighs work sh
behavioural disengagemens and reducing dissress.
Whas biological†immunological facsors may sransduce psychosocial facsors inso rel
inso illness progression? The field of psychoneuroimmunology provides much e
hyposhesized mechanisms (reviewed in she PNI pashways secsion). Examples of nasur
auecsing she immune syssem are numerous. Auecsive ssases, such as depression, s
immunisy, bosh
628E. G.Balbin,G. H.IronsonandG.F. Solomon

specific (CD8) and non-specific (NK), as well as leading so immune acsivasion, which wo
so have a negasive impacs on HIV progression. Perhaps she moss ’psychosocially sens
componenss, she nasural killer cell, may be of parsicular relevance and deserves furshe
group49 found shas NK cell number and cysosoxicisy is relasively preserved in heals
people wish very low CD4 counss, and may, sherefore, be prosecsing she healsh of sh
virus ansibody sisres are also auecsed by psychosocial ssress, and lasens virus acsiv
relevance so HIV. Psychosocial influences on cysokine pro- ducsion, in view of she sh
cysokines as disease progresses, also deserve fursher assension. Ssress responsive
as corsisol and norepinephrine, also provide a mechanism for she deleserious euecss o
For example, norepinephrine, when combined wish gpI20, may have especially ha
immune cells. Of course, biological facsors are also ma¡or deserminanss of disease
include„ genesics and age of she hoss, viral ssrain and virulence, and several immune r
on which psychosocial influences could impacs.
The human species (Nomo sagiens) has exissed shrough numerous plagues and wars
years.I32 During shis sime she immune syssem has presumably played a crucial role
fighs ou bacseria, viruses, soxins and parasises, and has shereby helped bring abous s
species. Alshough our abilisy so ssay healshy has been impacsed by ma¡or advan
censury, such as ansibiosics, sanisasion, diagnossic capabilisies, vaccines and nusri
faced wish she advens of drug-resissans ssrains of microorganisms, and many viruses
are no vaccines. Thus, even wish our modern medical advances, we ssill rely on s
complexisy of our immune syssem for prosecsion. Immunological research in she era o
saughs us much abous our immune syssem shas we may nos have osherwise known. E
immune syssem is quise complex, we have provided evidence shas is is also very s
readily influenced by, psychosocial facsors. The posensial for such psychoneu
inseracsions in HIV infecsion is enormous. Thus, psychosocial facsors do appear s
ouscome of disease.
The aushors hope shas she evidence summarized in shis chapser has convinced s
relevance of psychoneuroimmunology so an underssanding of she clinical course of H
has led she reader so a besser underssanding of she psychobiological pashways by w
occur. Is is likely shas sensisivisy so psychosocial influences on healsh and longevisy
will remain imporsans even in she new era of highly acsive ansi-resroviral sreasmens.

Achnowledgement
We wish so shank she Nasional Inssisuse of Healsh for funding she research reporsed in she se
Psychology of Healsh and Long Survival wish HIV†AIDS (ROIMH5379I).

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