Volume 8 – Number 1 © MBL Communications Inc.CNS Spectrums - January 2003
Does stress management affect psychological and immune
functioning in persons with human immunodeficiency virus
infections? Stress-management techniques, such as relaxation
training and imagery, cognitive restructuring, coping-skills
training, and interpersonal-skills training, may reduce anxi-
ety, depression, and social isolation in HIV-infected persons by
lowering physical tension and increasing a sense of control
and self-efficacy. A psychoneuroimmunologic model is pro-
posed wherein these psychological changes are hypothesized to
be accompanied by an improved ability to regulate neuroen-
docrine functioning, which in turn may be associated with a
partial normalization of immune system functions such as
lymphocyte proliferation and cytotoxicity, providing more effi-
cient surveillance of latent viruses that may contribute directly
to increased HIV replication and generate opportunistic infec-
tions or cancer if left unchecked. Such a normalization of
stress-associated immune system decrements are hypothesized
to forestall or minimize increases in viral load and expression
of clinical symptoms. This model is useful for testing the fac-
tors contributing to the health effects of stress-management
interventions in HIV-infected persons. In this context, one gen-
eral research strategy for testing the effects of stress-manage-
ment interventions is to target them toward the more prevalent
psychosocial challenges that HIV-infected people face at vari-
ous points in the disease process; enroll an HIV-infected popu-
lation (eg, HIV-positive homosexual and bisexual men) into a
randomized trial; and monitor changes in cognitive, affective,
behavioral, and social factors in parallel with hormonal,
immunologic, viral, and clinical changes over the course of
time. This article will review the major psychoneuroimmuno-
logic findings that have emerged using this paradigm and
suggest future research directions and clinical applications.
CNS Spectrums 2003;8(1):40-51
Once an individual is infected with human immunodefi-
ciency virus a period of clinical latency, lasting for a number
of years follows the initial sequence of primary infection,
viral dissemination, and development of HIV-specific immu-
nity. During the clinically latent period there continues to be
increasing viral load, depletion of T-helper/inducer cells
(cluster designation [CD] 4) in peripheral blood and associ-
ated loss of “immune repertoire,” and an increasing propor-
tion of HIV-infected lymphoid cells.1The decline in CD4
cells and related immunologic surveillance functions leaves
the infected person susceptible to a number of opportunistic
infections and cancers characterizing acquired immune defi-
ciency syndrome. Some of the more commonly observed
infections include pneumocystic carinii pneumonia, crypto-
coccal meningitis, and candida esophagitis.2
Many other diseases manifest in HIV-infected persons
are caused by ubiquitous herpes viruses (eg,
cytomegalovirus-associated retinitis is a major cause of
blindness in HIV-infected persons). HIV-infected persons
are also vulnerable to relatively rare cancers, including
Kaposi’s sarcoma and Burkitt’s lymphoma, and cervical car-
cinoma in women. Interestingly, these cancers are believed
to be promoted by fairly common viruses, such as human
papillomavirus types, which are associated with cervical
neoplasia and squamous cell cervical carcinoma.3,4
In sum, HIV-infected persons are extremely vulnerable
to a wide range of pathogens normally controlled by the
immune system and, with time, these individuals may con-
tract a number of life-threatening clinical conditions.
Behavioral-management techniques may help HIV-infected
persons cope with the psychosocial aspects of this chronic
disease. There is evidence that improving psychological
adaptation to HIV may also contribute to physical health
outcomes.5A major thrust for this research examines
processes underlying psychological adjustment. HIV infec-
tion presents multiple challenges that can create a state of
chronic stress, which may overwhelm an individual’s coping
resources and this can significantly impair their ability to
emotionally adjust to ongoing and future demands of the ill-
ness.6,7HIV-infected individuals are among the groups who
might benefit substantially from interventions that teach
them to cope with these chronic demands. By learning how
stress-reducing psychosocial interventions help people
adapt and adhere to important lifestyle changes, behavioral
specialists gain insight into ways to facilitate the coping
process in people facing this life-threatening condition.8
RATIONALE FOR USE OF STRESS
MANAGEMENT IN HIV INFECTION
Stress, Immunity, and HIV Infection
As in the case of other chronic diseases, HIV infection is
characterized by a disorder in one or more bodily systems.
Dr. Antoni is professor in the Department of Psychology and Psychiatry and Behavioral Sciences at the University of Miami in Coral Gables, Florida.
Disclosures: The work reported in this review was funded in part from National Institute of Mental Health grants P01 MH49548 and T32 MH18917.
Please direct all correspondence to: Michael H. Antoni, PhD, Department of Psychology, University of Miami, PO Box 248185, Coral Gables, FL. 33124;
Tel: 305-284-2522, Fax: 305-284-1366; E-mail: email@example.com.
Stress Management and
Psychoneuroimmunology in HIV Infection
By Michael H. Antoni, PhD
Here, symptoms are clinically manifest across long periods
of time as a function of the degree of immune system
impairment. In fact, HIV-infected people become ill from
the “complications” of their chronic disease not the disease
itself. Those who cannot retain adequate immune system
functioning go on to develop the life-threatening infections
or cancers that characterize the condition known as AIDS.
Dysregulated immune functions underlying HIV disease
may also be exacerbated by stressors.8Since stressors have
been shown to influence the immune system in healthy pop-
ulations, it is plausible that stress management interven-
tions may normalize immune status and provide health
benefits in HIV-infected people.6
Psychoneuroimmunologic (PNI) research, as applied to
HIV/AIDS, examines ways in which psychosocial influ-
ences, such as stressful life events, distress states, stress
moderators (eg, social support), and management tech-
niques modulate, immune system functioning, and ulti-
mately clinical disease course. Accordingly,
stress-management interventions that modify psychosocial
factors, such as risk behaviors, emotional distress, mal-
adaptive coping strategies, and social isolation, might also
modulate biological factors, such as certain endocrine and
immune system components. Our group has hypothesized
that these interventions might help the individual retard
the onset of disease complications by maintaining the
functioning of various immune cells (eg, CD4+ T-helper
lymphocytes and natural killer [NK] cells) within a range
necessary to defend against certain “opportunistic” infec-
tions and cancers. Since CD4+ cells are depleted in the
advancing stages of HIV infection,9increases in qualita-
tive aspects of HIV itself (eg, mutation and replication
rate)1and of lymphocytes (eg, proliferation [growth and
reproductive abilities] and cytotoxicity [recognition and
killing abilities]) might be important in predicting those
HIV+ individuals who do and do not develop opportunistic
infections quickly. In fact, it has been shown that HIV+
men and women who remain healthy despite having low
CD4+ cell counts have a relative preservation of natural
killer cell cytotoxicity (NKCC).10
The ability of lymphocytes to multiply when challenged
by antigens, often evaluated using tests of lymphocyte pro-
liferative responses to plant mitogens such as phyto-
hemagglutinin (PHA) may compensate to some degree for
the smaller number of CD4+ lymphocytes available as the
disease progresses. “Innate” immune functions, such as
NKCC, which is a largely CD4 cell-independent function,
may also compensate in protecting against viral infections
and neoplastic growth and metastasis. This may have par-
ticular relevance for surveillance of common latent
viruses, which can become life threatening in
HIV-infected persons.11Herpes viruses, such as
Epstein-Barr virus (EBV) or herpes simplex virus (HSV)
and human papilloma viruses (HPVs), such HPV 16
and 18, are often poorly controlled in the context of
HIV-induced defects in CD4+ cell-directed cytotoxic
function. Immune functions, such as NKCC, which may be
partially preserved in HIV infection (since NK cells lack
CD4+ attachment sites for HIV), may help to survey and
control these and other infections in the HIV-infected host.
Conversely, stress-induced impairments in NKCC as well
as cytotoxic T-cell functioning may permit virus reactiva-
tion to go unchecked in HIV-infected individuals12with
subsequent effects of HIV replication and progression to
AIDS,13,14as well a increased risk of virally related cancers
such as EBV-associated Burkitt’s lymphoma,15and HPV-
associated cervical cancer.4,16,17Because several of these
viruses are known to have immunosuppressive effects, in
and of themselves, reactivation of these viruses could have
implications for compounding HIV-induced immune sys-
tem decrements and, possibly, disease progression.18
STRESS HORMONES, PNI, AND HIV
Psychosocial factors are hypothesized to relate to the
immune system via several adrenal hormones, including
cortisol and catecholamines (norepinephrine [NE] and
epinephrine [EPI]), known to be altered as an function of
an individual’s appraisals of and coping responses to
stressors.19These hormones have most commonly been
associated with alterations in immune system functions,
such as lymphocyte proliferation and NKCC.8Some of
these hormones are also known to be dysregulated in
depressed individuals20and those reporting other psycho-
logical states, such as loneliness and social isolation.21
Stressors perceived as uncontrollable and social losses,
such as divorce and bereavement, have been related to
alterations in some of these immunomodulatory hor-
mones. These hormones appear to have a number of
effects in the context of HIV infection.
The HPA Axis and HIV
Although the literature is quite mixed, some work has
shown that glucocorticoids can enhance HIV replication
in vitro,22and may favor a shift from Th1 cytokines (eg, γ-
interferon) to Th2 cytokine (eg, interleukin [IL]-10) pro-
duction23—this pattern tending to work against the
maintenance of adequate surveillance of HIV and other
viral infections. HIV-infected persons display elevated
resting levels of cortisol,24muted cortisol responsivity to
cold pressor challenge25and corticotropin-releasing hor-
mone challenge,24and a flattened circadian rhythm for the
secretion of cortisol and other HPA hormones.26This set
of findings is consistent with physiologic regulatory
changes resulting from chronic stress and a low sense of
mastery, which may in turn result in chronically elevated
cortisol levels.19However, it should be kept in mind that
not all studies have found HIV status to be associated
with alterations in cortisol.
Furthermone, within HIV-infected persons, elevated corti-
sol levels have not always been found to be related to immune
measures, such as CD4 counts, or with the rate of disease pro-
gression. Factors, such as daily diurnal fluctuations, disease
Volume 8 – Number 1 © MBL Communications Inc. CNS Spectrums - January 2003
15. Boshoff C, Weiss R. AIDS-related malignancies. Nat Rev Cancer. 2002;2:373-382.
16. Byrnes D, Antoni MH, Goodkin K, et al. Stressful events, pessimism, natural
killer cell cytotoxicity and cytotoxic/suppressor T cells in HIV+ Black women
at risk for cervical cancer. Psychosom Med. 1998;60:714-722.
17. Pereira D, Antoni MH, Simon T, et al. Stress and squamous intraepithelial
lesions in women with human papillomavirus and human immunodeficiency
virus. Psychosom Med. In press.
18. Griffiths PD, Grundy JE. Molecular biology and immunology of
cytomegalovirus. J Biochem (Tokyo). 1987;241:313-324.
19. McEwen B. Protective and damaging effects of stress mediators. N Engl J
20. Calabrese J, King M, Gold P. Alterations in immunocompetence during stress,
bereavement, and depression: focus on neuroendocrine regulation. Am J
21. Kiecolt-Glaser J, Ricker D, George J, et al. Urinary cortisol levels, cellular
immunocompetency, and loneliness in psychiatric inpatients. Psychosom Med.
22. Markham P, Salahuddin S, Veren K, Orndorff S, Gallo R. Hydrocortisone and
some other hormones enhance the expression of HTLV-III. Int J Cancer.
23. Clerici M,Trabattoni D, Piconi S, et al. A possible role for the cortisol/anticor-
tisols imbalance in the progression of human immunodeficiency virus.
Psychoneuroendocrinology. 1997;22(suppl 1):S27-S31.
24. Lortholary O, Christeff N, Casassus P et al. Hypothalamic-pituitary-adrenal
function in human immunodeficiency virus-infected men. J Clin Endocrin
25. Kumar M, Kumar A, Morgan R, Szapocznik J, Eisdorfer C. Abnormal pitu-
itary-adrenocortical response in early HIV-1 infection. J Acquir Immune Defic
26. Rondanelli M, Solerte S, Fioravanti M, et al. Circadian secretory pattern of
growth hormone, insulin-like growth factor type I, cortisol, adrenocorticotropic
hormone, thyroid-stimulating hormone, and prolactin during HIV infection.
AIDS Res Hum Retroviruses. 1997;13:1243-1249.
27. Plaut M. Lymphocyte hormone receptors. Annu Rev Immunol. 1987;5:621-669.
28. Manuck S, Cohen S, Rabin B. Individual differences in cellular immune
responses to stress. Psychol Sci. 1991:2:111-115.
30. Cole S, Korin Y, Fahey J, Zack J. Norepinephrine accelerates HIV replication
via protein kinase-A dependent effects on cytokine production. J Immunol.
31. Webster E, Elenkov I, Chrousos G. The role of corticotropin-releasing hormone
in neuroendocrine-immune interactions. Mol Psychiatry. 1997;2:368-372.
32. Cole S, Kemeny M. Psychosocial influences on the progression of HIV infec-
tion. In: Ader R, Cohen N, Felten D, eds. Psychoneuroimmunology. 3rd ed.
New York, NY: Academic Press; 2001:583-612
33. Cole S, Kemeny M, Naliboff B, Fahey J, Zack J. ANS enhancement of HIV
pathogenesis. Brain Behav Immun. 2001;15:121.
34. Maier SF, Watkins LR, Fleshner M. Psychoneuroimmunology: the interface
between behavior, brain, and immunity. Am Psychol. 1994;49:1004-1017.
35. Ironson G, Antoni MH, Schneiderman N, et al. Coping: interventions for opti-
mal disease management. In: Chesney M, Antoni MH, eds. Health Psychology
Innovations: New Target Populations for Prevention and Care. Washington,
DC: American Psychological Association; 2002:167-196.
36. Coates T, McKusick L, Stites D, Kuno R. Stress management training reduced
number of sexual partners but did not improve immune function in men infect-
ed with HIV. Am J Public Health. 1989;79:885-887.
37. Auerbach JH, Oleson TD, Solomon GF. A behavioral medicine intervention as an
adjunctive treatment for HIV-related illness. Psychol Health. 1992;6:325-334.
38. Simons A, Garfield S, Murphy G. The process of change in cognitive therapy
and pharmacotherapy: changes in mood and cognition. Arch Gen Psychiatry.
39. Folkman S, Chesney M, McKusick L, et al. Translating coping theory into
intervention. In: J. Eckenrode, ed. The Social Context of Stress. New York, NY:
40. Antoni MH. Cognitive behavioral stress management for gay men learning of
their HIV-1 antibody test results. In: Spira J, ed. Group Therapy for Patients
With Chronic Medical Diseases. New York, NY: Guilford Press; 1997:55-91.
41.Antoni MH, Ironson G, Lutgendorf S. Psychosocial intervention in HIV infec-
tion. In: Nott K, Vedhara K, eds. Psychosocial And Biomedical Interactions in
HIV Infection. Amsterdam, Netherlands: Harwood Academic Publishers;
42. Antoni MH, Baggett L, Ironson G, et al. Cognitive behavioral stress management
intervention buffers distress responses and immunologic changes following noti-
fication of HIV-1 seropositivity. J Consult Clin Psychol. 1991;59:906-915.
43. Esterling B, Antoni M, Schneiderman N, et al. Psychosocial modulation of
antibody to Epstein-Barr viral capsid antigen and herpes virus type-6 in HIV-
1 infected and at-risk gay men. Psychosom Med. 1992;54:354-371.
44. Antoni MH, Lutgendorf S, Ironson G, Fletcher MA, Schneiderman N. CBSM
intervention effects on social support, coping, depression and immune func-
tion in symptomatic HIV-infected men [abstract]. Psychosom Med.
45. LaPerriere A, Antoni MH, Schneiderman N, et al. Exercise intervention atten-
uates emotional distress and natural killer cell decrements following notifica-
tion of positive serologic status for HIV-1. Biofeedback Self Regul.
46. Cruess D, Antoni MH, Schneiderman N, et al. Cognitive behavioral stress
management effects on DHEA-S and serum cortisol in HIV seropositive men.
47. Cruess D, Antoni MH, Schneiderman N, et al. Cognitive behavioral stress
management increases free testosterone and decreases psychological distress
in HIV seropositive men. Health Psychol. 2000;19:12-20.
48. Cruess D, Antoni MH, Kumar M, Schneiderman N. Reductions in salivary
cortisol are associated with mood improvement during relaxation training
among HIV-1 seropositive men. J Behav Med. 2000;23:107-122.
49 Cruess S, Antoni MH, Cruess D, et al. Reductions in HSV-2 antibody titers
after cognitive behavioral stress management and relationships with neuroen-
docrine function, relaxation skills, and social support in HIV+ gay men.
Psychosom Med. 2000;62:828-837.
50. Antoni MH, Wagner S, Cruess D, et al. Cognitive behavioral stress manage-
ment reduces distress and 24-hour urinary free cortisol among symptomatic
HIV-infected gay men. Ann Behav Med. 2000;22:29-37.
51. Antoni MH, Cruess D, Wagner S, et al. Cognitive behavioral stress manage-
ment effects on anxiety, 24-hour urinary catecholamine output, and T-cytotox-
ic/suppressor cells over time among symptomatic HIV-infected gay men. J
Consult Clin Psychol. 2000;68:31-45.
52. Antoni MH, Cruess D, Klimas N, et al. Stress management and immune sys-
tem reconstitution in symptomatic HIV-infected gay men over time: effects on
transitional naïve T-cells (CD4+CD45RA+CD29+). Am J Psychiatry.
53. Kubler-Ross E. On Death and Dying. New York, NY: MacMillan; 1969.
54. Lechner S, Antoni MH, Lydston D, et al. Cognitive-behavioral interventions
improve quality of life in women with AIDS. J Psychosom Res. In press.
56. Friedman A, Antoni MH, Ironson G, et al. Behavioral interventions, changes
in perceived social support and depression following notification of HIV-1
seropositivity. Paper presented at: Annual Meeting of the Society of Behavioral
Medicine; April, 1991; Washington, DC.
57. Lutgendorf S, Antoni MH, Schneiderman N, Ironson G, Fletcher MA.
Psychosocial interventions and quality of life changes across the HIV spec-
trum. In: Baum A, Dimsdale J, eds. Perspectives in Behavioral Medicine.
Lawrence Elbaum Associates, Inc.: Mahwah, NJ; 1994:205-239.
58. Kelly J, Murphy D, Bahr R, et al. Outcome of cognitive-behavioral and support
group brief therapies for depressed, HIV-infected persons. Am J Psychiatry.
59. Mulder CL, Emmelkamp P, Antoni MH, et al. Cognitive-behavioral and expe-
riential group psychotherapy for HIV-infected homosexual men: a comparative
study. Psychosom Med. 1994;56:423-431.
60. Chesney MA, Folkman S, Chambers D. Coping effectiveness training for men
living with HIV: preliminary findings. Int J STD AIDS. 1996;7(suppl 2):75-82.
61. Goodkin K, Tuttle R, Blaney NT, et al. A bereavement support group interven-
tion is associated with immunological changes in HIV-1+ and HIV-1-homo-
sexual men [abstract]. Psychosom Med. 1996;58:83-84.
Volume 8 – Number 1 © MBL Communications Inc. CNS Spectrums - January 2003
62. Goodkin K, Feaster D, Asthana D, et al. A bereavement support group inter-
vention is longitudinally associated with salutary effects on the CD4 cell count
and number of physician visits. Clin Diagn Lab Immunol. 1998;5:382-391.
63. Goodkin K, Baldewicz T, Asthana DP, et al. A bereavement support group
intervention affects plasma burden of HIV-1. J Hum Virol. 2001;4:44-54.
64. Lutgendorf S, Antoni M, Ironson G, et al. Changes in cognitive coping skills
and social support during cognitive behavioral stress management interven-
tion and distress outcomes in symptomatic human immunodeficiency virus
(HIV)-seropositive gay men. Psychosom Med. 1998;60:204-214.
65. Cruess S, Antoni MH, Hayes A, et al. Changes in mood and depressive symp-
toms and related change processes during cognitive behavioral stress manage-
ment in HIV-infected men. Cognit Ther Res. 2002;26:373-392.
66. Antoni MH, Lehman J, Kilbourn K, et al. Cognitive-behavioral stress manage-
ment intervention decreases the prevalence of depression and enhances bene-
fit finding among women under treatment for early-stage breast cancer. Health
67. Yang JY, Schwartz A, Henderson EE. Inhibition of 3’ azido-3’ deoxythymi-
dine-resistant HIV-1 infection by dehydroepiandrosterone in vitro. Biochem
Biophys Res Commun. 1994;201:1424-1432.
68. Yang JY, Schwartz A, Henderson EE. Inhibition of HIV-1 latency reactivation
by dehydroepiandrosterone (DHEA) and an analog of DHEA. AIDS Res Hum
69. Ironson G, AntoniM Lutgendorf S. Can psychological interventions affect immu-
nity and survival? Present findings and suggested targets with a focus on cancer
and human immunodeficiency virus. Adv Mind Body Med. 1995;1:85-110.
70. Ironson G, Field T, Scafidi F, et al. Massage therapy is associated with
enhancement of the immune systems cytotoxic capacity. Int J Neurosci.
71. Madden K, Sanders V, Felten D. Catecholamine influences and sympathetic
neural modulation of immune responsiveness. Annu Rev Pharmacol Toxicol.
72. Mills P, Ziegler M, Patterson T, et al. Plasma catecholamine and lymphocyte
beta 2-adrenergic receptor alterations in elderly Alzheimer caregivers under
stress. Psychosom Med. 1997;59:251-256.
73. Landmann R. Beta-adrenergic receptors in human leukocyte subpopulations.
European Journal of Clinical Investigations [abstract]. 1992;22(suppl 1):30.
74. Felten, D. Changes in the neural innervation of lymphoid tissues with age.
In: Hall N, Altman F, Blumenthal S, eds. Mind-Body Interactions and Disease
and Psychoneuroimmunological Aspects of Health and Disease. Washington,
DC: Health Dateline Press; 1996:157-164.
75. Maher K, Klimas N, Dickinson G, et al. T lymphocyte subsets and Highly
Active Antiretroviral Therapy (HAART) of HIV infection. Applications in
Clinical Cytometry. In press.
76. Musey L, Hughes J, Schacker T. Cytotoxic T-cell responses, viral load and dis-
ease progression in early human immunodeficiency virus type I infection.
N Engl J Med. 1997;337:1267-1274.
77. Picker L, Treer J, Ferguson-Darnell B, et al. Control of lymphocyte recircula-
tion in man. I. Differential regulation of the peripheral lymph node homing
receptor L-Selectin on T cells during the virgin to memory cell transition.
J Immunol. 1993;150:1105-1121.
78. Connors M, Kovacs J, Krevat S, et al. HIV infection induces changes in
CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire
that are not immediately restored by antiviral or immune-based therapies.
Nat Med. 1997;3:533-540.
79. West-Edwards C, Pereira D, Greenwood D,et al. An investigation of the psy-
chological and immune effects of a cognitive behavioral stress management
(CBSM) intervention for HIV+ African American women [abstract]. Ann
Behav Med. 2001;23:12.
80. Markowitz JC, Kocsis JH, Fishman B, et al. Treatment of depressive symptoms
in human immunodeficiency virus-positive patients. Arch Gen Psychiatry.
81. Ekstrand M, Chesney M. Adhering to complex medication regimens.
In: Chesney M, Antoni MH, eds. Health Psychology Innovations: New Target
Populations for Prevention and Care. Washington, DC: American
Psychological Association; 2002:283-306
82. Schneiderman N, Antoni MH, Ironson G. Cognitive behavioral stress manage-
ment and secondary prevention in HIV/AIDS. Psychology and AIDS
83. Motivala S, Hurwitz B, Antoni MH, et al. Psychological distress is associated
with decreased memory T-cells and B-cells in pre-AIDS HIV seropositive men
and women. Psychosom Med. In press.
84. Spiegel D, Bloom GC, Kraemer JS, Gottheil E. Effect of psychosocial treat-
ment on survival of patients with metastatic breast cancer. Lancet.
85. Goodwin P, Leszcz M, Ennis M, et al. The effect of group psychosocial support
on survival in metastatic breast cancer. N Engl J Med. 2001;345:1719-1726.
Volume 8 – Number 1 © MBL Communications Inc.CNS Spectrums - January 2003