Psychoneuroimmunology and HIV Disease Progression

Among psychiatrists who treat patients with HIV/AIDS, the question of how psychosocial distress effects the progression of HIV disease is likely to arise. Even for healthy individuals, we are only beginning to clarify the complex pathways by which thoughts and emotions impact immune function. Due to the bidirectionality of the communications of the brain and the immune system, this is a complicated scenario. The fact that HIV alters the function of the immune system during the course of its progression creates greater confounds to the understanding of these systems. We will address the rationale that progression from HIV infection to AIDS may be modulated by psychosocial factors, discuss possible reasons for conflicting findings and posit some clinically relevant recommendations drawn from research findings.

Psychosocial Variables: Modulators of HIV Disease Progression?

The progression of HIV disease is highly variable among individuals. Factors known to play a role in determining the rate of progression include the viral strain, genetic characteristics of the host immune system, co-infections with other pathogenic organisms (Zorilla et al., 1996) and health maintenance habits (e.g., diet, exercise, medical treatment). However, these factors do not fully explain the extreme degree of variability noted in the course of HIV disease (Cole and Kemeny, 1997).

Given that certain immune parameters are modulated by physiologic mediators of the stress response (i.e., catecholamines and glucocorticoid hormones), it would seem logical to investigate the role of stress and other psychosocial factors in the progression of HIV infection. In fact, changes in immune function and disease susceptibility have been well documented in healthy individuals during times of psychic distress (Ader et al., 1995; Miller et al., 1997), and studies over the past 15 years have shown significant correlations between psychosocial variables and HIV progression. However, there have also been a number of studies showing no such correlation.

Stressful Life Experiences. Studies examining stressful life events and HIV have shown interesting but conflicting results. For example, Rabkin et al. (1991) studied 124 HIV-positive men and found no association between clinician-rated anxiety and CD4+ lymphocyte counts at study entry and at six-month follow-up. However, Evans et al. (1995), performing a similar cross-sectional study of HIV-positive men, did show a significant correlation between increased frequency of negative life events over the six months prior to interview and decreased CD8+ cytotoxic T-cells. Evans et al. (1997) continued with a two-year prospective study and found that not only were severe life stressors predictive of greater declines in some lymphocyte populations (natural killer [NK] cells and CD8+ cytotoxic lymphocytes), but also that such stressors increased the rate of HIV progression to AIDS. The researchers emphasized that their results were noted only in those experiencing severe life stress, not stresses associated with everyday living. For every severe life stress reported, they found the risk of HIV disease progression to AIDS doubled. In their most recent work, these investigators followed 82 HIV-positive gay men at six-month intervals for up to 5.5 years. They found that more cumulative life stress and less cumulative social support doubled or tripled the probability of progressing to AIDS (Leserman et al., 1999).

Depression. Studies examining the effect of depression on HIV progression have had variable results. For example, Rabkin et al. (1991) found no correlation in their cross-sectional study between depression and CD4+ lymphocyte count or stage of HIV illness; however, a relationship was found between clinician-rated depression and increased report of HIV-related symptoms. In 1993, Burack et al. reported findings of a five-year prospective cohort study that showed a significant correlation between depressive symptoms and more rapid decline in CD4+ lymphocyte counts, although not with increased HIV/AIDS-related morbidity or mortality. Conversely, in a similar eight-year study of 1,809 HIV-positive gay men, Lyketsos et al. (1993) found no significant relationship between depression and indicators of HIV disease progression or clinical outcome. Likewise, results from a seven-year prospective cohort study of 402 gay men showed that depressed affect was associated with a greater AIDS-related mortality rate, although no correlation was found for measures of CD4+ lymphocytes (Mayne et al., 1996). In a meta-analytic review, Zorilla et al. (1996) concluded that no significant correlations could be made between depressive symptoms and markers of HIV disease progression. There did seem to be a relationship between depression and increased reporting of HIV-related symptoms.

Social Interaction. It is widely accepted that social isolation is a significant risk factor for several disease entities and that significant interruptions in social relationships can have deleterious effects. With regard to HIV/AIDS, this is exemplified among studies examining the death of an intimate partner, an event generally associated with bereavement and social role disruption.

Kemeny et al. (1995) studied 39 HIV-positive gay men who had experienced the death of an intimate partner within the previous 13 months. Looking at various markers of HIV progression pre- and postbereavement, they found significant increases in serum neopterin (a product of activated monocytes and a predictor of HIV disease progression) in the bereaved group. This finding was independent of ratings of depression, suggesting a qualitative difference between bereavement and depressive disorders. Another study unexpectedly found that greater self-reports of loneliness were associated with a slower decline in CD4+ lymphocytes over a three-year period, but not associated with time to AIDS diagnosis or AIDS-related death (Miller et al., 1997).

Similarly, in a study of socially and independently housed rhesus monkeys, Capatinio and Lerche (1998) found that greater social disruption around the time of inoculation with simian immunodeficiency virus correlated with a significantly increased rate of mortality. The rate of mortality also increased after inoculation if the animal was placed in a novel social environment versus individual housing. These findings, although yielding a variability of findings, suggest that social interactions may play an increasingly important role in understanding HIV disease progression.

Coping Responses. There is growing evidence that one's coping style may modulate the progression of HIV infection. For example, in a study by Byrnes et al. (1998), an increased measure of pessimism was related to lower NK-cell cytotoxicity in a group of HIV-seropositive black women at risk for cervical cancer. Furthering this hypothesis, Cole et al. (1996) found in a nine-year study that the degree of "closetedness," or concealment of gay identity, was strongly correlated with more rapid decline of CD4+ lymphocytes, more rapid progression to AIDS diagnosis and more rapid time to AIDS-related mortality. These findings were unrelated to health practices, medical treatment or other demographic differences and suggest a relationship between disease progression, poor coping and the stress of concealing one's sexual orientation.

Examining specific coping styles in a group of 74 gay men diagnosed with AIDS, Reed et al. (1994) showed that higher measures of "realistic acceptance" of their AIDS diagnosis was a significant predictor of decreased survival time. They point out that, in the past, researchers have shown unrealistic optimism to be associated with better psychological adjustment and more active coping styles. Studies of the converse of this idea have found a "fighting spirit" to be associated with reduced progression to AIDS over a 12-month period (Solano et al., 1993). In an examination of the impact of perceived causes of events on HIV progression, Segerstrom et al. (1996) showed that the tendency to attribute negative events to the self was predictive of faster CD4+ lymphocyte decline over the 18-month study period.

Factors Contributing to the Differences Observed in Studies to Date

In attempting to compare the studies cited above, confounding elements include both the heterogeneity of the study populations and methodological differences among investigators. The majority of studies have been conducted among groups consisting primarily of Caucasian, well-educated, homosexual men living in metropolitan locations. However, even within this subgroup, there are variables that might skew study data (e.g., age group, unknown time since HIV infection, access to antiretroviral treatment and so forth).

A variety of methodological difficulties deserve mention. HIV/AIDS is an illness with an extraordinarily long latency period, so following patients even for several years may yield no substantive change in disease status. Putative immunologic changes brought about by psychosocial factors tend to be small, necessitating larger samples to reveal significant findings (Cole et al., 1997). Many psychiatric disorders tend to be recurring, time-limited entities, and our measurement techniques for these typically yield only a cross-sectional glimpse of mental health at a given time. These factors could preclude significant findings in a disease like HIV/AIDS, which has a lengthy asymptomatic phase (Zorilla et al., 1996).

Currently, several known laboratory findings correlate with HIV progression, but their predictive value is questionable. The most common marker, the CD4+ lymphocyte, is predictive of increased risk for opportunistic infections once it drops below a critical level. Another promising marker is the plasma viral load. However, with the advent of newer antiretroviral therapies, CD4+ lymphocyte levels can rise markedly and viral load can become undetectable for years.

Clinical Recommendations and Applications: Lengthier Studies are Needed

Many studies give us hope that psychosocial interventions can not only improve our patients' quality of life, but also improve their physical health. For example, a study of 10 HIV-positive men by Taylor (1995), showed that behavioral stress management over a 20-week period significantly slowed the rate of CD4+ lymphocyte decline. These results are tempered by conflicting findings such as those of Mulder et al. (1995). Working with 26 asymptomatic, HIV-positive men in either cognitive-behavioral group therapy or experiential group therapy, these researchers found no significant differences in CD4+ lymphocyte changes between group members and controls over a 24-month period. Lengthier studies of larger populations are clearly needed to elucidate further findings and to translate them from laboratory data into real-world scenarios.

Exercise training has been studied among several HIV-positive cohorts, revealing numerous psychological benefits including decreases in anxiety and depression and increases in active, positive coping styles. In a review of pertinent literature, LaPerriere et al. (1997) concluded that a typical regimen of aerobic exercise can result in increases in CD4+ lymphocyte counts in all HIV-positive patients, except those with AIDS. However, even among AIDS patients, the CD4+ lymphocyte counts remained stable over an 18-month study (whereas control patients' levels continued to decline).

The impact of HIV on neural tissue remains questionable. There is evidence, at least in the case of depression, that HIV-positive individuals respond to antidepressant therapy at rates similar to seronegative controls. The side-effect profiles of these medications also seem to differ minimally based on HIV status (Rabkin et al., 1994).

A significant finding about HIV and depression in the meta-analysis by Zorilla and colleagues (1996) was that depression was associated with increased reporting of HIV physical symptoms, regardless of objective markers of physical disease. Depressed HIV-positive individuals may have a more painful experience of HIV illness, regardless of objective physical signs and markers. Also, alleviating depression in some cases may facilitate compliance with medication regimens and medical follow-up, improve self-care, and decrease self-destructive behavior-all variables associated with diminished morbidity and mortality (Stober et al., 1997).

Overall, evidence remains inconclusive regarding the role of psychosocial factors in HIV disease progression, as well as the long-term effectiveness of interventions directed at such factors. However, it is certain that psychiatric disorders and social stressors occur frequently during the course of HIV disease. While it is unclear whether specific psychiatric and psychosocial interventions will extend life or improve physical health among HIV/AIDS patients, we do know definitively that treatment can alleviate psychiatric disorders, relieve distress, and improve quality of life and such critical variables as treatment adherence.

With more HIV-positive individuals being seen in general psychiatric practice, one should not underestimate the positive effects of comprehensive psychiatric care.

References:

References

1.

Ader R, Cohen N, Felton D (1995), Psychoneuroimmunology: Interactions between the nervous system and the immune system. Lancet 345(8942):99-103.

2.

Burack JH, Barrett DC, Stall RD et al. (1993), Depressive symptoms and CD4 lymphocyte decline among HIV infected men. JAMA 270(21):2568-2573.

3.

Byrnes DM, Antoni MH, Goodkin K et al. (1998), Stressful events, pessimism, natural killer cell cytotoxicity, and cytotoxic/suppressor T cells in HIV+ black women at risk for cervical cancer. Psychosom Med 60(6):714-722.

4.

Capatinio JP, Lerche NW (1998), Social separation, housing relocation, and survival in simian AIDS: a retrospective analysis. Psychosom Med 60(3):235-244.

5.

Cole SW, Kemeny ME, Taylor SE et al. (1996), Accelerated course of human immunodeficiency virus infection in gay men who conceal their homosexual identity. Psychosom Med 58(3):219-231.

6.

Cole SW, Kemeny ME (1997), Psychobiology of HIV infection. Crit Rev Neurobiol 11(4):289-321.

7.

Cole SW, Kemeny ME, Taylor SE (1997), Social identity and physical health: accelerated HIV progression in rejection-sensitive gay men. J Pers Soc Psychol 72(2):320-335.

8.

Evans DL, Leserman J, Perkins DO et al. (1997), Severe life stress as a predictor or early disease progression in HIV infection. Am J Psychiatry 154(5):630-634.

9.

Evans DL, Leserman J, Perkins DO et al. (1995), Stress associated reductions of cytotoxic T-lymphocytes and natural killer cells in asymptomatic HIV infection. Am J Psychiatry 152(4):543-548.

10.

Kemeny ME, Weiner H, Duran R et al. (1995), Immune system changes after the death of a partner in HIV-positive gay men. Psychosom Med 57(6):547-554.

11.

LaPerriere A, Klimas N, Fletcher MA et al. (1997), Change in CD4+ cell enumeration following aerobic exercise training in HIV-1 disease: possible mechanisms and practical applications. Int J Sports Med 18(Suppl 1):S56-S61.

12.

Leserman J, Jackson ED, Petitto JM et al. (1999), Progression to AIDS: The effects of stress, depressive symptoms, and social support. Psychosom Med 61(3):397-406.

13.

Lyketsos CG, Hoover DR, Guccione M et al. (1993), Depressive symptoms as predictors of medical outcomes in HIV infection. JAMA 270(21):2563-2567 [see comments].

14.

Mayne TJ, Vittinghoff E, Chesney M et al. (1996), Depressive affect and survival among gay and bisexual men infected with HIV. Arch Intern Med 156(19):2333-2338.

15.

Miller GE, Kemeny ME, Taylor SE et al. (1997), Social relationships and immune processes in HIV seropositive gay and bisexual men. Ann Behav Med 19(2):139-151.

16.

Mulder CL, Antoni MH, Emmelkamp PM et al. (1995), Psychosocial group intervention and the rate of decline of immunological parameters in asymptomatic HIV-infected homosexual men. Psychother Psychosom 63(3-4):185-192.

17.

Rabkin JG, Rabkin R, Harrison W, Wagner G (1994), Effect of Imipramine on mood and enumerative measures of immune status in depressed patients with HIV illness. Am J Psychiatry 151(4):516-523.

18.

Rabkin JG, Williams J, Remien RH et al. (1991), Depression, distress, lymphocyte subsets, and human immunodeficiency virus symptoms on two occasions in HIV-positive homosexual men. Arch Gen Psychiatry 48(2):111-119.

20.

Reed GM, Kemeny ME, Taylor SE et al. (1994), Realistic acceptance as a predictor of decreased survival time in gay men with AIDS. Health Psychol 13(4):299-307.

21.

Segerstrom SC, Taylor SE, Kemeny ME et al. (1996), Causal attributions predict rate of immune decline in HIV-seropositive gay men. Health Psychol 15(6):485-493.

22.

Solano L, Costa M, Salvati S et al. (1993), Psychosocial factors and clinical evolution in HIV-1 infection: a longitudinal study. J Psychosom Res 37(1):39-44.

23.

Stober DR, Schwartz JAJ, McDaniel JS et al. (1997), Depression and HIV disease: prevalence, correlates and treatment. Psychiatric Annals 27(5):372-377.

24.

Taylor DN (1995), Effects of a behavioral stress-management program on anxiety, mood, self-esteem, and T-cell count in HIV-positive men. Psychol Rep 76(2):451-457.

25.

Zorilla EP, McKay JR, Luborsky L, Schmidt K (1996), Relation of stressors and depressive symptoms to clinical progression of viral illness. Am J Psychiatry 153(5):626-635.