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Psychosomatic Medicine 70:555-561 (2008)
© 2008 American Psychosomatic Society

PSYCHOSOCIAL INFLUENCES

Coping as a Multisystem Construct Associated With Pathways Mediating HIV-Relevant Immune Function and Disease Progression

Lydia R. Temoshok, PhD, Rebecca L. Wald, PhD, Stephen Synowski, PhD and Alfredo Garzino-Demo, PhD

From the Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland.

Address correspondence and reprint requests to Lydia R. Temoshok, Department of Medicine, University of Maryland School of Medicine, and The Institute of Human Virology, 725 West Lombard Street, Baltimore, MD 21201. E-mail: temoshok{at}umbi.umd.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 NOTES
 REFERENCES
 
We review psychoneuroimmunological research linking coping with HIV disease progression and its indicators, as well as with viral and host factors that may mediate or contribute to HIV progression. Our perspective on coping broadly encompasses the attempts of multiple mental and biological systems to adapt to changing internal and environmental conditions and to reestablish homeostasis. Accordingly, we discuss studies within four dimensions of coping: cognitive (appraisals, expectancies, and explanatory style), emotional (the Type C coping pattern and related constructs), active-passive strategies and behavior patterns, and physiological (autonomic reactivity and recovery). Finally, we present a model that integrates key studies linking coping with HIV prognostic indicators and clinical disease progression. Based on empirical evidence, the model suggests plausible mechanisms by which coping may be connected to HIV progression/antiprogression factors and immunopathogenesis to affect HIV clinical progression.

Key Words: coping • Type C • HIV/AIDS • chemokines • psychoneuroimmunology • immune activation

Abbreviations: PNI = psychoneuroimmunologic; ANS = autonomic nervous system; HPA = hypothalamic-pituitary-adrenal.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
NOTES
 REFERENCES
 
Thetheoretical possibility of psychoneuroimmunologic (PNI) influences on the course of disease in HIV/AIDS was suggested early in the history of the epidemic (1). Subsequently, a number of studies have demonstrated relationships between various psychosocial variables and outcome-related immunological parameters, typically CD4+ cell counts (2), or HIV disease progression (3–5). The most common independent variables in the HIV PNI literature have included stressors, coping, and depression. The primary effects of stress, depression, and its theoretical opposite—positive psychosocial factors—are reviewed elsewhere in this issue (6,7).

This review will focus on an intrinsically related yet distinct topic: the means by which persons with HIV respond to and cope with the stressors they face, and how these coping responses relate to immune function and HIV progression. Coping was initially conceptualized by Lazarus (8) as an essentially cognitive process consisting of threat and resource appraisal and the active selection of coping responses. McEwen’s concept of allostasis expands this definition of coping to include the ability to achieve stability through change by engaging the autonomic nervous system (ANS), the hypothalamic-pituitary-adrenal (HPA) axis, and the cardiovascular, metabolic, and immune systems to respond to internal and external stressors (9–11). McEwen’s perspective on coping is congruent with our (Temoshok’s) theoretical views on coping or adaptation as encompassing the attempts of multiple mental and biological systems (cognitive, emotional, behavioral, social, immunological, hormonal, cardiovascular, etc.) to adapt to changing internal and environmental conditions, including stressors, and to reestablish homeostasis (12–16).

In the first section of this paper, we discuss key PNI studies of coping, immune function, and HIV progression, considered within four dimensions or domains of coping: cognitive, emotional, passive-active, and physiological. The review summarizes recent and ongoing research concerning our expanded concept of coping as it relates to HIV clinical progression, indicators of progression, and potential biological mediators that may inhibit or enhance progression. Finally, we will present a model that integrates key studies linking coping with HIV prognostic indicators and clinical disease progression. Based on these studies, the model suggests plausible mechanisms by which coping processes may be connected to HIV progression/antiprogression factors and immunopathogenesis to influence HIV clinical progression.

Coping, Immune Function, and HIV Disease Progression
Appraisals, Expectancies, and Explanatory Style: Cognitive Dimension of Coping
A primary focus of PNI research has been the examination of dispositional interpretive styles, such as optimism and pessimism. To the extent that these styles affect how individuals appraise stressors and select responses, they may be considered cognitively based coping styles. One study of 85 HIV-positive gay men found that the potent stressor of bereavement was only associated with CD4+ cell decline, the most widely used prognostic indicator, when reactions to bereavement involved depressive interpretive styles, particularly self-reproach. Grief reactions that did not involve these maladaptive cognitions were not associated with either CD4+ count or symptom onset (17). A related finding in 72 gay men was that bereavement was only associated with earlier onset of HIV symptoms during a 3-year follow-up when it occurred in the presence of negative expectancies regarding HIV (18). Similarly, a general tendency to attribute negative events to the self was found to be correlated with faster CD4+ cell decline in 86 gay men during 18 months (19). Pessimism has also been associated with higher viral load at 18-month follow-up in 412 people with HIV (20). This effect was not moderated by poorer adherence to antiretroviral therapy or greater levels of negative health behaviors, suggesting that it is the mental state of pessimism itself, not pessimistic behavioral choices, which seems to have a negative impact on immune function. In a cross-sectional study of 36 African-American women co-infected with HIV and human papillomavirus (HPV), a pessimistic interpretation of life stressors, rather than the number or severity of life stressors, was related to lower natural killer cell cytotoxicity and a lower percentage of cytotoxic CD8+ lymphocytes (21).

Although pessimism and negative expectancies or self-attributions have been linked to deleterious immune function in patients with HIV, the influence of the presumed opposite construct of optimism on HIV outcomes is less clear. An optimistic outlook has been associated with lower mortality (n = 31 men) (22) and slower HIV disease progression (n = 177 men and women) (23), whereas other studies have found no effect (n = 74 men) (24) or even negative health effects (25). In the latter study (n = 47 HIV-infected men), an optimistic explanatory style for life events was found to predict greater declines in CD4+ count over a 2-year follow-up when initial CD4+ count was controlled, whereas "dispositional optimism" was unrelated to CD4+ counts (25). Unrealistic optimism can be harmful, as illustrated in a study (n = 412 HIV infected men and women) that found a curvilinear relationship between optimism and CD4+ cell decline; the highest CD4+ counts at follow-up were associated with moderate amounts of optimism (20). Thus, one explanation for the mixed findings regarding optimism may be that what is termed "optimism" represents a combination of healthy, adaptive positive outlook and what is considered "maladaptive" denial—or at least minimization. Rather than representing a genuinely positive outlook, unrealistic optimism may reflect a repressive coping style (see below for a discussion of the Type C coping style) or the inability to recognize or realistically appraise stressors in the environment. It is easy to conjecture how inappropriate optimism could engender such clearly deleterious health behaviors as ignoring medical recommendations for diagnostic tests, follow-up examinations, and/or prescribed medications, which, in turn, could lead to negative HIV outcomes (26).

Ironson et al. (23) provided a related interpretation of the mixed findings in the literature, suggesting that optimism may have the most beneficial results when it spurs proactive, problem-focused coping strategies. Their study of 177 HIV positive men and women found that relationships between optimism and disease progression were mediated by coping, with optimists showing greater levels of proactive behavior, less avoidant coping, and less depression. In contrast, optimism in the absence of positive coping skills may result in greater disappointment or distress when negative life events inevitably occur.

Some other predominantly cognitive coping strategies have been found to be related to HIV outcomes. Successful efforts to find meaning in response to HIV-related stressors were associated with lower mortality during 2- to 3-year follow-up (n = 40 gay men) (27). Proactive problem-solving was associated with slower disease progression in 104 men and women (28) and 65 gay men (29) with HIV.

Emotional Dimension of Coping: Type C Coping Pattern and Related Constructs
Type C coping, first described in the context of malignant melanoma (13,30–33), is a fragile dimension of coping characterized, in the extreme, by the repression, nonrecognition, and nonexpression of emotion, with a focus on others’ needs to the exclusion of one’s own (34,35). Stronger Type C coping has been associated with discrepancies between physiological indicators of stress and reported emotional perturbation, indicating the nonrecognition of physiologically manifested stress (36).

Components of Type C coping have been associated with unfavorable changes in immune parameters relevant to progression among men with symptomatic HIV infection (1,37,38). In an Italian study of 100 HIV-positive men and women, originally asymptomatic HIV-positive individuals with stronger Type C coping were more likely to develop symptoms of AIDS at 6- and 12-month follow-up (39). A later replication with a larger sample (n = 200) indicated that the association between Type C coping and disease progression was dependent on disease context (40). Type C coping significantly predicted progression in patients with baseline CD4+ counts between 200 and 499 cells/mm3 (40), counts considered "midstage" in the HIV disease process (41); Type C was unrelated to disease progression in patients with CD4+ counts >500 cells/mm3 at baseline (40), counts reflecting "early stage" disease (41). The authors hypothesized that as CD4+ counts decline and symptoms appear, individuals are challenged to mobilize active coping resources to address changing health status and to explore treatment options. Those with strong Type C coping may be less able to recognize their increased levels of physiological and psychological stress, and therefore are less likely to cope effectively and proactively in this situation. In contrast, in the early stage of disease, HIV may not represent that significant a stressor such that the effectiveness of coping matters; thus, Type C coping in a less stressful situation would be less likely to have a negative impact on immune and clinical parameters.

In an ongoing study of 200 HIV-positive, predominantly African-American outpatients (both men and women), stronger Type C coping was significantly associated with higher in vitro antigen-stimulated production of the proinflammatory cytokine interleukin-6 (IL-6) at baseline, controlling for age and CD4+ count (42). Considered an HIV progression factor, IL-6 can induce HIV replication in monocytes in vitro (43), up-regulate the CCR5 HIV coreceptor to facilitate entry of R5 viruses (the dominantly transmitted strain), increase HIV replication via (most likely) increased immune activation, and induce apoptosis—all of which are associated with accelerated HIV progression (44). Thus, the association of Type C coping and IL-6 (42) suggests that chronically and/or stress-related increased production of IL-6 may be a candidate mediator for the previously reported relationship between stronger Type C coping and subsequent disease progression (39,40).

In addition to the Type C construct, difficulties expressing and processing emotion have been associated with decreased immune function and faster HIV disease progression. Long-term survivors with HIV (n = 46) were distinguished from an equivalent seropositive comparison group (n = 89) by their emotional expressiveness and the depth of their processing of past traumas (45). Among female patients in that study, emotional expressiveness was related to higher CD4+ counts and lower viral loads, and "deep processing" was associated with higher CD4+ counts. The key finding of this study was that emotional material must be deeply processed rather than simply expressed. Supporting this conclusion, one study (n = 65) showed that persons with HIV who relied heavily on "venting" (expressing emotional distress without processing) to relieve stress experienced a greater increase in HIV-related physical symptoms over a 1-year period (46).

Persons with alexithymia ("no words for feelings") are characterized as having externally oriented thinking as well as deficits in the cognitive processing and regulation of emotion, resulting in difficulties in describing and identifying feelings (47). Unlike strong Type C copers, however, who are not conscious of being distressed, alexithymic individuals may report undifferentiated and diffuse psychological distress, such as "being upset" (48). In a sample of 200 HIV-infected men and women, higher total alexithymia scores were associated with significantly lower antigen-stimulated production of macrophage inflammatory protein (MIP)-1{alpha} when cells were stimulated in vitro by p24, the HIV core protein (42). The β-chemokines MIP-1{alpha} and MIP-1β bind to the HIV coreceptor CCR5, thus blocking cell entry by R5 viral strains (the most common HIV strains, particularly earlier in infection) and suppressing of HIV replication (49–52). Increased production of these β-chemokines is associated with a more favorable and AIDS-free clinical status and decreased risk of disease progression (53–56).

Active-Passive Dimension of Coping: Strategies and Behavior Patterns
Faster progression to AIDS has been linked to the use of passive coping strategies, such as denial or disengagement (39,57–61). In the largest of these studies, Ironson and colleagues followed 177 men and women for 2 years and found that persistent avoidant coping was associated with 1.7 times greater loss of CD4+ count and 6 times greater increase in viral load compared with those with low avoidance (58). Antoni and colleagues found that HIV-infected gay men scoring above, compared with below, the median on passive coping strategies, had lower CD4/CD8 ratios and lower lymphocyte proliferative response to phytohemagglutinin (PHA) both at 3 weeks and 1 year after serostatus notification (59). The passive coping strategies (e.g., denial, behavioral and mental disengagement) were more predictive of immunological change than the active coping approaches (e.g., positive reinterpretation and growth). Leserman et al. showed faster progression to AIDS during 7.5 years among 82 HIV infected gay men with high persistent denial scores (60). Ironson et al. also found that increases in denial from pre to post serostatus notification were associated with a greater probability of becoming symptomatic and developing AIDS during a 2-year follow-up study of 23 gay men (61). A study by Solano and colleagues of 100 male and female HIV-infected individuals found that those with higher denial and lower fighting spirit at baseline were more likely to become symptomatic after 1 year (39).

Concealment of homosexual identity, a related concept to denial, has been associated with an accelerated course of HIV infection in 80 gay men followed for 9 years (62). An ashamed, repressive coping style, including a strong emphasis on the importance of concealing one’s HIV status, has been associated with lower CD4+ counts in a study of 273 HIV positive inpatients and outpatients (63). A helpless/hopeless, overwhelmed reaction, representing the failure of coping, was also associated with lower CD4+ counts as well as with higher viral loads in this same study. Furthermore, patients with this hopeless reaction were also more likely to be hospitalized for HIV during the 6-month follow-up period (63).

In contrast to these findings, active, assertive, and expressive coping styles have been associated with more favorable health indicators or outcomes. Disclosure of both sexual orientation and HIV status was associated with improvement in CD4+ counts over time in 373 psychiatric outpatients (64). An active, appropriately assertive style of coping was associated with decreased HIV progression over a 1-year period in 51 gay men (65). Along similar lines, a large longitudinal study of 773 HIV-positive women found that an array of coping-related variables designated as "psychological resources" (positive affect, positive expectancies regarding health outcomes, and the ability to find meaning in challenging circumstances) were associated with slower CD4+ count decline and less mortality during the 5-year follow-up period (66). Positive coping factors and their relationship to HIV progression are discussed more thoroughly in another paper in this issue (7).

Physiological Dimension of Coping: Autonomic Reactivity and Recovery
The often-observed relationship between stress and immunity (6) may be moderated by the effects of suboptimal coping on sympathetic nervous system responses to stress and on overactivity of adrenal steroids, which in turn modulate the expression of cytokines and chemokines (67). A combination of biological and psychological factors may be involved in the sympathoimmune anomalies seen as HIV-positive individuals attempt to cope with stress (68). The HPA axis and sympathetic nervous system regulation of cortisol, epinephrine, and norepinephrine may be involved in the relationship between coping and HIV progression via effects on leukocyte biology (69). The ANS neurotransmitter norepinephrine can accelerate HIV replication in vitro (70). Preliminary results from a sample of 21 early-stage HIV-infected men being treated with HAART provide suggestive evidence that individuals with higher ANS activity had significantly higher residual viral replication (71). In vitro analyses in the same study showed that norepinephrine up-regulated cellular expression of both HIV coreceptors CXCR4 and CCR5, and increased viral gene expression in previously infected cells (71).

An early study undertaken in the pre-HAART era examined patterns of heart rate (HR) response to an emotional mental stressor in 25 men with clinically defined AIDS (72,73). As hypothesized, Temoshok and colleagues found that a moderate increase in HR consistent with the experimental stressor, followed by a full or approximate return to the individual’s resting baseline, was the strongest and most significant predictor of longer survival, controlling for baseline CD4+ cell count and AIDS-defining condition (72,73). This pattern of HR response was postulated to represent "adaptive homeostasis" (15). Consistent with these preliminary findings, Temoshok and colleagues reported that greater HR reactivity and poorer HR recovery in response to experimental stressors were each significantly associated with lower production of the HIV-inhibiting β-chemokine MIP-1{alpha}, adjusted for cardiovascular medications, methadone use, CD4+ count and age, in regression analyses of 140 HIV-infected men and women (42). These effects were independent of the significant association of alexithymia and MIP-1{alpha}.

Theoretical Integration: Hypothesizing a Model of Coping Connections to HIV Progression and Antiprogression Factors, Immunopathogenesis, and HIV Clinical Progression
Figure 1 presents a summary of key findings reviewed in this paper concerning the hypothesized linkages between coping factors and HIV disease progression, indicators of progression (HIV-1 RNA or viral load and CD4+ cells/µL or mm3 (CD4+ count)), and HIV progression/antiprogression factors that may be mediators of clinical progression (e.g., anti-HIV β-chemokines, HIV-stimulating IL-6, and other proinflammatory cytokines). This hypothesized model is not intended to be a comprehensive summary of all possible linkages and mechanisms.


Figure 16
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  		Figure 1. Hypothesized model: multifactorial contributions of coping to HIV progression/antiprogression factors, immunopathogenesis, and HIV-1 progression. The long lines and arrows connect coping factors that have been shown in the majority of studies reviewed here to be associated with increased (solid lines) or decreased (dashed lines) HIV clinical disease progression or its indicators. The small black boxes indicate where there is preliminary evidence for biological mediators linking coping factors with HIV progression, investigated in only a few studies. PIC = proinflammatory cytokines; IL-6 = interleukin-6; TNF{alpha} = tumor necrosis factor {alpha}.

 

Considering potential mechanisms of progression, biomedical HIV research points strongly to immune activation, depicted in the bold ellipse in the lower center of Figure 1, as playing a pivotal role in HIV immunogenesis and progression. Immune activation up-regulates the CCR5 coreceptor, increases HIV-1 replication, and induces inappropriate activation-induced apoptosis (cell death)—all of which are associated with accelerated disease progression (44). A new perspective on the immune effects of chronic stress has emphasized the importance of dysregulation of the balanced response between proinflammatory cytokines (PIC), particularly IL-6, and anti-inflammatory cytokines when faced with immunological challenges (74). Consistent with this view of the dysregulating effects of chronic stress, the PIC IL-6 is shown in Figure 1 as enhancing immune activation, which both up-regulates the HIV coreceptor CCR5, and significantly, stimulates HIV replication, which leads to HIV clinical progression. In this paper, we have reviewed recent evidence that stronger Type C coping in early to mid-stage HIV-infected individuals is associated with increased production of IL-6 (42), which is a plausible mediator of the previously observed associations between Type C coping and HIV disease progression (39,40).

The hypothesized model in Figure 1 depicts linkages between coping factors and β-chemokines that are considered to be HIV antiprogression or protective factors (49–56,75). We have reviewed recent research showing that more regulated or homeostatic autonomic (HR) responses to experimental stressors are associated with increased stimulated β-chemokine production, whereas alexithymia is significantly associated with decreased production (42). There has been no research to date, to our knowledge, on the connection between coping or other psychological factors and other known antiprogression factors such as Th1 cytokines (e.g., Interferon-gamma) or CD8+ factors (75).

Research and Clinical Implications: A Concluding Comment on Causality
The paucity of research on potential mediators of the more frequently reported connections between coping factors and HIV disease progression or its indicators is surprising. In a related context (research on psychosocial interventions and cancer), we highlighted the importance of basing psychosocial interventions intended to affect positive disease outcomes on evidence for plausible mechanisms linking disease outcomes and psychosocial factors to be modified by the intervention (76). We proposed the term psychogenicity to refer to the demonstrated ability of an intervention to produce hypothesized psychological changes that have been demonstrated to be associated with more favorable biomedical outcomes or processes (77). One cannot reasonably conclude that an intervention caused or even contributed to a favorable clinical outcome, even in a randomized controlled trial, unless it was demonstrated that the intervention reliably modified immune or other mechanisms shown in previous or concurrent biological studies to affect clinical outcomes. Thus, studies of potential mediators of the associations between coping factors and HIV clinical disease progression bring us one step closer to suggesting causality.

With a clearer idea of causal links, we are also one step closer to developing and testing interventions that can positively affect mediators of HIV progression, and subsequently, clinical status and disease progression. On this basis, we would recommend that evidence-based assessments of how patients cope over time with HIV, its treatment, and other stressors—undertaken in collaboration with behavioral medicine/psychosocial clinical investigators—should be a component of standard HIV medical care. In conclusion, although there is accumulating evidence that passive, emotionally repressive/nonexpressive, pessimistic/hopeless, and physiologically dysregulated coping responses or styles may have a detrimental impact on HIV clinical disease progression, we need more studies to elucidate the potential mediators of these biopsychosocial relationships.


   NOTES
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 ABSTRACT
 INTRODUCTION
 NOTES
REFERENCES
 
Received for publication July 16, 2007; revision received February 18, 2008.

Supported in part by National Institutes of Health Grant R01 HD048154 (L.T.).

This paper is dedicated to the late Dr. Bernard H. Fox and Dr. George S. Solomon, whose contributions to behavioral medicine and psychoneuroimmunology were immense and will always be remembered.

DOI:10.1097/PSY.0b013e318177354f


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 NOTES
 REFERENCES
 

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