Intertwinement of Body and Mind:
Potential Biological Pathways Linking Prolonged Psychosocial Stress to HIV Disease Progression in the Era of Effective Antiretroviral Treatment
Name: Louisa Wagner
Student Number: 6338623/ 10081127 Supervisor: Jos Bosch
Word Count: 5681 Date: 4.6.2014
Contents
Abstract p. 3
Introduction p. 4 -‐ 7
The HPA axis as a possible underlying mechanisms of the association between adverse psychosocial factors and HIV disease progression
p. 8 -‐ 10 The SNS as a possible underlying mechanisms of the association
between adverse psychosocial factors and HIV disease progression
p. 10 -‐ 12 Immune mechanisms that mediate the relationship between adverse
psychological factors and HIV disease progression
p. 13 -‐ 17
Conclusion & Discussion p. 17 -‐ 20
Literature p. 21-‐ 26
Abstract
Several studies have demonstrated that prolonged psychological stress is associated with HIV disease progression even in the era of effective antiretroviral treatment, the underlying mechanisms are not yet well
understood. This thesis examines the biological mechanism linking prolonged psychosocial stress to HIV disease. First, it considers whether the stress
hormone cortisol released by the HPA axis functions as a mediator. Results are inconsistent over whether cortisol is at all related to HIV disease progression. Second, the SNS is considered as a potential mediator. This review gives consistent support that there is an association between SNS activity,
psychosocial stress and HIV disease progression. Furthermore, heightened SNS activity has shown to mediate the influence of psychosocial risk factors on HIV disease progression in animals. Third, it is examined whether immune
mechanisms act as mediators. The studies evaluated herein provide evidence that there is an association between adverse psychosocial factors, immune mechanisms, and HIV disease progression. It therefore might be clinically relevant to assess both psychological stress levels and these biological markers in patients starting antiretroviral medication.
Intertwinement of Body and Mind: Potential Biological Pathways Linking Prolonged Psychosocial Stress to HIV Disease Progression in the Era of
Effective Antiretroviral Treatment
The acquired immune deficiency syndrome (AIDS) is a disease of the human immune system caused by the chronic infection with human immune deficiency virus (HIV). Until today HIV/AIDS remains a global epidemic with an estimated 35 million people living with HIV and 2.3 million new infections per year (http://www.unaids.org). In developed countries the incidence of HIV has declined as a result of HIV education, good screening and effective treatment. However, in North America there are still 1.3 million people living with HIV/AIDS and there were 20.000 AIDS related deaths in 2012. It therefore remains important to better understand which factors influence the progression of HIV.
HIV progresses by infecting CD4+ T-‐cells, whose task it is to direct other immune cells to carry out their functions (Klimas, O’ Brian, Koneru, & Fletcher, 2008). An infection with HIV causes CD4+ cell numbers to decrease, as the immune system becomes increasingly impaired and the level of HIV in the blood increases (viral load). The pace of this decline varies per case. Factors that influence the progression include comorbid diseases, age, genes, the use of antiretroviral therapy (ART) and ART adherence (Sloan, Collado-‐Hidalgo, & Cole, 2007b).
Since the introduction of the most commonly used ART in 1996, highly active antiretroviral therapy (HAART), the morbidity and mortality rate among HIV positive persons has been reduced, raising the life expectancy to such an extent that the disease is now considered chronic rather than terminal (Klimas et al., 2008). Despite these positive results, there is still variability between the life expectancy of HIV-‐infected individuals undergoing adequate and constant medical treatment (Leserman & Temoshok, 2011). Some people remain healthy for years, while in others HIV progresses more quickly in spite of the use of ART. Moreover, only a fraction of the discrepancy in HIV progression was explained by the above-‐mentioned factors, comorbid diseases, age, genes, use of ART and ART adherence (Sloan et al., 2007b).
It has been hypothesized that psychosocial stress could explain some of the variability in accelerated HIV progression in those on an adequate medical regimen. According to the Kop en Gottdiener (2012) psychosocial factors can be divided into three categories: acute (e.g. acute distress, outburst of anger, mental activity), episodic (e.g. depression, exhaustion, episodes of distress related to job loss or divorce, lasting for several weeks to two years) and chronic (e.g.
personality traits, coping mechanism, socio-‐environmental circumstances). Several studies have linked episodic and chronic psychosocial risk factors to HIV disease progression in the present era of HAART (Chida & Vedhara, 2009; Leserman, 2008), but which biological processes underlie this link is not yet well known. Therefore, this thesis will explore possible biological pathways
underlying the link between psychosocial stress factors and HIV disease progression.
This idea of psychosocial factors influencing the onset and progression of diseases has already existed for centuries (Kemeny & Schedloswki, 2007). Hans Selye is considered the first who defined the mechanisms of stress-‐induced bodily responses (1956). The stress response begins in the brain, when someone experiences a stressful event, a signal will be sent to the hypothalamus, which can activate two different pathways: the sympathetic nervous system (SNS) and the hypothalamus-‐pituitary-‐adrenal axis (HPA axis). The activation of the SNS results in the release of two stress hormones, epinephrine and norepinephrine. The second pathway of the stress response system is the HPA axis resulting in the release of the stress hormone cortisol. In response to stress these hormones can affect the immune system. The cells of the immune system are called
leukocytes, white blood cells, which defend the body against both infectious diseases and foreign invaders. One of the important subtype of leukocyte are the natural killer cells (NK cells), which can break up and destroy any type of virally infected cells or cancer cells. Another important component are signalling molecules, cytokines, which regulate the immune response. There are different types of cytokines: pro-‐inflammatory cytokines, which can stimulate
inflammation, and anti-‐inflammatory cytokines, which inhibit inflammation. Interleukin 6 (Il-‐6) is a pro-‐inflammatory cytokine, released in the acute phase of inflammation. IL-‐6 can lead to worsening of a disease by increasing the
activation of the immune system, for instance producing fever (Gleeson & Bosch, 2013). Stress hormones can also influence the production of these cytokines. Furthermore, stress hormones can have an effect on the trafficking of immune cells causing them to move differently, sending them for example directly to the lymph nodes to be released in the emergency situation. Lastly, stress can have an effect on the activity of the cells, for example it can suppress the functioning of natural killer cells (Cole et al., 2008).
While it seems that acute stress elevates the level of these stress
hormones and may prevent excessive immune activation, episodic and chronic psychosocial stress factors can stimulate the SNS and the HPA axis leading to continued release of stress hormones, which in turn might act on immune cell trafficking and activation. The continued release of these stress-‐hormones might supress the immune system. What might follow is a less adequate immune
response to anti-‐inflammatory signals from these hormones, and an expansion of inflammatory processes, possibly making HIV infected people more susceptible to HIV progression (Cole, 2008).
Several previous studies have demonstrated that psychosocial factors can influence the immune system. For example, it was demonstrated that students who were more chronically stressed and lonely due to examinations had
significant lower levels of NK cell activity (Kiecolt-‐Glaser et al., 1984). Moreover, the effect of adverse psychosocial factors on the immune system was shown to be clinically relevant, influencing disease outcomes. According to research, chronically stressed people exposed to a cold virus had an increased risk of infection compared to their non-‐stressed counterparts (Cohen, Tyrell, & Smith, 1991). Furthermore, a meta-‐analysis by Walburn et al. (2009) has shown that the duration of the wound healing process negatively correlates with depression and psychological stress. Thus, there is evidence that psychosocial stress factors can impact disease outcomes. In this thesis it will be discussed whether
psychosocial factors influence HIV disease Progression through the HPA axis, the SNS and the immune system.
It is especially important to address psychosocial risk factors and to understand their influences better in HIV infected individuals, since they are faced with many psychosocial challenges, such as the HIV test results
notifications, the outbreak of the first symptoms, lifestyle and interpersonal changes, medication side-‐effects, adherence to medication, etcetera. There is also evidence that HIV infected people have twice the risk of being diagnosed with depression (Carrico, Antoni, Young, & Gorman, 2008). Therefore, it can be speculated that if an HIV patient becomes stressed or depressed, life quality and health status will decrease. A better understanding of the underlying
mechanisms, which link adverse psychosocial factors to HIV disease progression, will help manage the disease even more successfully by possibly leading to the development of new psychological and pharmacological diagnostic, screening and treatment options. These new developments could improve psychological adjustment and enhance health status by modulating the communication between the SNS axis, HPA axis and the immune system leading to great increases in the patient's quality of life and life span.
This review will focus first on the HPA axis and the SNS as possible pathways underlying the association between adverse psychosocial factors and HIV progression. Finally, this thesis will discuss immune mechanisms, in
particular NK cell and the IL-‐6 cytokine, as a possible mediator of the
relationship between adverse psychosocial factors and HIV disease severity. In general it is expected that episodic and chronic psychosocial stress factors will alter the immune response, and suppress it, while acute factors can have an enhancing effect (bidirectional theory of stress). Furthermore, the effect of prolonged psychosocial stress on HIV disease progression is examined in the era of effective antiviral treatment, therefore all the participants in the studies are undergoing ART, if not mentioned differently.
The HPA-‐axis as a possible underlying mechanisms of the association between adverse psychosocial factors and HIV disease progression.
The HPA axis releases the stress hormone cortisol, which can inhibit the immune response and can influence cytokine production and leukocyte trafficking. In this paragraph it is discussed whether cortisol serves as a possible mechanism underlying the association between adverse psychosocial factors and HIV disease progression.
In a study of 128 untreated HIV infected persons it was researched whether cortisol patterns were associated with CD4 cell count (Patterson et al., 2013). Cortisol patterns were assessed 3 times a day: immediately after waking, 30 minutes thereafter, and before going to sleep at night. The authors found that a greater decline in cortisol during the day was associated with fewer CD4 cells. Lower waking cortisol levels correlated with greater decline in CD4 cells, a risk factor for HIV progression. Cortisol is the highest while waking and gradually declines over the course of the day, this rhythm can be changed when exposed to chronic stress or depression, resulting in lower waking cortisol and less decline during the day. These data suggest that the HPA axis could represent an
important pathway through which psychosocial risk factors could influence HIV progression.
In a nine-‐year longitudinal study this hypothesis, suggesting that an alteration in cortisol represents a pathway explaining the association between psychosocial risk factors and HIV progression, was further examined (Leserman et al., 2002). In the study, stressful life events, social support, depressive
symptoms, and plasma cortisol level were assessed amongst 96 HIV infected men twice a year. Subjects in this study were not undergoing effective
antiretroviral treatment at study entry. These episodic and chronic psychosocial factors were measured with self-‐report questionnaires; the concentration of cortisol was measured with a commercial RIA kit (assessing salivary cortisol). The results of this study demonstrate that these psychosocial factors and a high level cortisol predicted HIV disease progression. Even though cortisol
independently predicted disease progression and mortality, it did not statistically mediate the association between disease progression and
psychosocial risk factor. Therefore it can only be concluded that there is a relationship between these factors.
The following study by Ironson et al. (2008) demonstrated different findings. In the 2-‐year longitudinal study, examined the relation between perceived stress, cortisol and HIV progression. Perceived stress was measured with a self-‐report questionnaire, and a 15-‐hour urinary cortisol collection was assessed every 6 months on 55 HIV infected individuals starting a new
antiretroviral protease inhibitor. The results showed that higher perceived stress predicted a higher viral load and poorer response to the new antiviral treatment. Cortisol, however, was not associated with disease outcome (viral load).
According to the study of Ironson et al. (2008) it can be concluded that cortisol is not related with HIV progression. These findings are inconsistent with the studies of Leserman et al. (2002) and Patterson et al (2013). Potential
methodological explanations for the discrepancy in the results could be that in the Leserman et al. (2002) study, salivary cortisol was used as opposed to the urinary cortisol measured in Ironson et al (2008) study. Furthermore, the studies (Leserman et al, 2002; Patterson et al., 2013) had a larger sample size, which increases the likelihood of detecting differences. Lastly, subjects in the studies from Leserman et al. (2002) and Patterson et al. (2013) were not undergoing antiretroviral treatment at study entry or during any other part of the study, in which sense it again differs quite strongly from the study conducted by Ironson et al. (2008). This could mean that cortisol might only have an effect on HIV
progression when patients are not undergoing antiretroviral treatment.
To draw a conclusion about whether different activation of the HPA axis represents a cause or a consequence of HIV disease progression, experimental studies are needed. Since human subjects cannot be randomly assigned to adverse psychosocial situations due to ethical constraints, it is more challenging to research the causality. However, researchers can use intervention studies to see if the intervention, which improves the psychosocial conditions of patients, will have an effect on the activation of the HPA axis and therefore on their health status.
Stress management interventions help people to efficiently cope with stressors and therefore reduce depressed moods and distress symptoms. It is
hypothesized that stress management techniques will also normalize HPA axis activity, such as the cortisol level. In a 10-‐week long study, 25 men were
randomly assigned to a cognitive behavioral stress management (CBSM, n = 16) intervention or to a waiting list (n = 9), controlling carefully for medical, socio-‐ demographic and behavioral characteristics (Antoni et al., 2005). Authors assessed depression with the depression with self-‐report questionnaire, urinary free cortisol and CD4 cell count at baseline, after the intervention period and at the 12 month follow up. Results showed that, compared to the control group, the CBSM intervention group showed greater reduction in depressed moods, and cortisol output. The data indicate that CBSM reduces not only depressed moods, but also cortisol output. It can be implied that CBSM, while reducing cortisol levels as well as depressed moods, leads to a better health status in HIV infected individuals. The study sample, however, was relatively small. Findings would need to be replicated to draw a stronger conclusion over the relevance of cortisol as a mediator between psychosocial factors and HIV disease progression.
In conclusion, these studies support the previously found results by Chida and Vedhara (2009) that adverse psychosocial factors are associated with
accelerated HIV progression. However, findings are inconsistent with regards to whether there is a relation between cortisol and HIV disease outcome. In general, there is not enough evidence to answer the question of whether episodic and chronic psychosocial stress factors dysregulate or suppress immune functioning through the continued release of cortisol by the HPA axis.
The SNS as a possible underlying mechanism of the association between adverse psychosocial factors and HIV disease progression
The sympathetic nervous system (SNS) has been known to modulate the immune system by releasing epinephrine, and norepinephrine, which can inhibit
pathways that normally activate the immune response. Episodic and chronic psychosocial stress factors can stimulate the SNS leading to continued release of these stress hormones, which in turn might act on immune cell trafficking and activation. In this paragraph it is discussed whether the release of these stress-‐
hormones might down-‐regulate the immune system, making HIV infected people more susceptible to HIV progression (Cole et al., 2008).
The following three studies provide consistent evidence that there is a relationship between psychosocial factors, SNS activity and HIV progression. The first study by Cole et al. (2003) examined the association between chronic
psychosocial factors (social inhibition), HIV progression and SNS activity. There is evidence that individuals with inhibited psychosocial characteristics (i.e. introversion, shyness, unassertiveness, emotional inexpressiveness,
passive/resigned responses to threat, social withdrawal) have heightened SNS activity (Cole et al., 2003). However, it has been unknown whether social inhibition is a psychological risk factor in HIV progression and whether
difference in SNS activity plays a mediating role herein. In the study of Cole et al. (2003), 54 HIV infected individuals were assessed three times over a period of 11-‐12 months. Social inhibition was measured with a combination of different self-‐report questionnaires measuring introversion, social avoidance and emotional inexpression. SNS activity was assessed by skin conductance, blood pressure, and pulse peak time. HIV progression was measured by CD4+ cell count. The results demonstrated that socially inhibited individuals displayed a decrease in CD4+ cells and poorer response to HAART. Heightened SNS activity in socially inhibited individuals was also associated with the outcome. Those effects, however, were not explained by other variables such as health behavior, demographics, and adherence. Most importantly, 60-‐90% of the total association between social inhibition and HIV viral load was explained by individual
differences in SNS activity. These data provide the first evidence that there is a relationship between heightened SNS activity and social inhibition and HIV progression.
Another way to measure SNS activity is to assess the stress hormone norepinephrine directly. A second study directly tested the associations between norepinephrine (NE), psychological stress, an episodic psychosocial stress factor, and HIV progression (Ironson et al., 2008). In this 2-‐year
longitudinal study with 55 people starting a new antiretroviral protease inhibitor, higher perceived stress (measured with a self-‐report questionnaire), and higher norepinephrine, predicted a higher viral load and a poorer response
to the new antiviral treatment. Moreover, the data show that NE statistically mediates the association between perceived stress and viral load, meaning that when perceived stress and NE were used as a predictor variable, perceived stress was no longer associated with viral load, but NE maintained this
association. Thus, consistent with results in the first study by Cole et al. (2003), variations in SNS activity are associated with a poorer response to antiretroviral treatment and HIV progression, and individual differences in SNS activity
possibly mediate this relationship.
Thirdly, an in vitro study by Collado-‐Hidalgo, Sung, and Cole, 2006,
exploring whether norepinephrine administration to HIV infected leukocytes can enhance viral replication in HIV, revealed that norepinephrine administration indeed enhances cellular vulnerability to infection and accelerates HIV
replication while suppressing antiviral cytokine responses. Together those three studies give further evidence that episodic and chronic adverse psychosocial factors can activate the SNS pathway, which in turn enhances HIV progression.
To confirm a causal relationship, experimental studies are needed, but ethical constrains prevent such experimental research in human subjects. Animal models provide researchers with the chance to assess tissues and to experimentally infect the animal, as well as to manipulate the social environment. In such an experimental study, rhesus macaque monkeys were experimentally infected with Simian Immunodeficiency Virus (SIV), the analogue to the human HIV virus, and randomly assigned to chronically stressful (social threat) or to stable environments (Sloan et al., 2007a). Given that HIV predominantly replicates in lymphoid organs and immune responses are initiated there, these tissues were examined. Results showed that social stress increases SNS
activation in lymphoid tissue in ways that facilitate viral replication. Thus in response to stress more norepinephrine is released into the lymph nodes which can lead to alteration in immune functioning directly related to disease
progression.
In summary, natural history studies, in vitro studies, and experimental animal models have consistently linked increased SNS activity as well as episodic and chronic psychosocial stress to HIV progression. Furthermore, the
heightened SNS activity might serve as a possible mediator between
psychosocial risk factors and HIV disease progression. The continued release of stress hormones might suppress the immune system; the following paragraph discusses the role of immune mechanisms as possible explanatory variables of the relationship between adverse psychosocial factors and HIV disease
progression.
Immune mechanisms that mediate the relationship between adverse psychosocial factors and HIV disease severity
Adverse psychosocial factors might accelerate HIV progression through further affecting immune mechanisms. First, this paragraph will discuss the effect of natural killer cells, a potential immunological mediator, which can break up and destroy HIV infected cells directly. Second, the influences of cytokines, in
particular Il-‐6, will be discussed, which can lead to worsening of a disease by increasing the activation of the immune system, for instance producing fever (Gleeson & Bosch, 2013).
Natural Killer Cells
Natural Killer (NK) cells are very sensitive to stress and psychosocial changes (Alter & Altfeld, 2006). Continued psychosocial stress could therefore lead to poorer responsiveness of NK cells (a sign low activation of the immune system), which in turn could lead to a greater risk of progressive HIV
immunodeficiency and mortality. NK cells are easily measured and therefore often used as an indicator of the immune system. There are two ways to measure NK cells. First, NK cells they can be counted, which is a quick and adequate measurement. However, the NK cell count does not measure the functional activity of one NK cell to kill virally infected cells. Therefore a second method can be used, in vitro tests, in which researchers stimulate blood in a test tube to see how fast NK cells can kill virally infected cells.
It is hypothesized that acute psychosocial stress in comparison to
person for the moment from outside pathogens (Gleeson & Bosch, 2013). A study by Hurwitz et al. (2005) examined whether acute mental stress induces a
mobilization of NK cell count in 133 HIV + subjects compared to 92 HIV-‐
subjects. Acute mental stress was induced by an evaluative speech task, in which subjects had to prepare and present a speech to defend themselves against the wrongful accusation of shoplifting. Before and after the task perceived mental stress was measured by a self-‐report questionnaire. A blood sample was taking through a catheter at baseline, every two minutes throughout the task, and every five minutes after the task was completed. The results showed that NK cell numbers were increased as a reaction to the acute stress in both the HIV+ and the HIV-‐ group. However, in comparison with the HIV-‐ group, the HIV+ group showed less stress-‐induced increases in NK cell count. These results indicate a more blunted increase in NK cell count in reaction to acute stress. This can be explained by the effect HIV has on the function NK cells in general.
In comparison, it is hypothesized that episodic psychosocial stress leads to poorer responsiveness of NK cells and to progression of HIV. In a 2-‐year prospective cohort study of 57 HIV infected women, it was examined whether improvement in depression is related to increases in NK cell activity (Cruess et al., 2005). A psychiatric clinician assessed the diagnostic status of depression with the Structured Clinical Interview for DSM-‐III-‐R (SCID) and with the
Hamilton Depression Rating Scale at study entry and followed up every 6 months across the 2-‐year period. A blood sample was taken at the same time to measure NK cell activity and viral load. The results demonstrated an association between major depression and diminished NK cell activity. Furthermore, these alterations in NK cells were reversible: in particular the resolution of major depression was related to increases in NK cell activity over time. These results imply that there is an association between depression and NK cell activation. This study provides further evidence supporting the hypothesis that episodic adverse psychosocial factors are related to certain aspects of innate immunity (NK cells), which are relevant to delaying the progression of HIV.
These two studies showed as hypothesized that acute stress and the resolution of episodic stress is related to an increase of NK cell over time. Whether the dsyregulation of NK cells due to episodic psychosocial stress
factors is actually strong enough to lead to HIV progression is examined in the following study. In a cross-‐sectional study of 200 HIV infected people it is tested whether alterations in NK cells mediate the relationship between greater
psychological distress and greater HIV disease severity (Greeson et al., 2008). Since it is also possible that HIV and the related immune cell alteration, such as NK cell activation can influence greater distress (Brabers and Nottet, 2006), it is also examined whether variations in greater psychological distress is influenced by HIV disease related alteration in NK cells (reverse directionality hypothesis). In this study, psychological distress referrers to subjective appraisal of life stress, HIV/AIDS related anxiety and depressive symptoms, which are all
measured by self-‐report questionnaires. Blood samples were drawn to measure the NK cell count, and viral load, and CD4 cell count. Analyses showed that there is an association between higher psychological distress level and greater
disease severity (higher viral load, lower CD4 cell count) and decreased NK cells. Furthermore, authors fitted the data in two models, which statistically analyze the mediating relationship of NK cells. The results showed that the data did not fit in the reverse directionality model, but into the hypothesized model, in which NK cells statistically mediates the relationship between psychological distress and HIV disease severity.
In conclusion, the two studies by Cruess et al. (2005) and Greeson et al. (2008) provide evidence that episodic psychosocial stress factors are related to an lower NK cell count, and NK cell activity. Furthermore, Greeson et al. (2008) provides evidence that psychosocial stress factors are also related to HIV disease progression, and NK cell might underlie this relationship. Finally, the study by Hurwitz et al. (2005) provides evidence that acute stress is related to a general increase in NK cell count, which was shown to be blunted in HIV
infected subjects. To my knowledge there is no research done on the influence of chronic psychosocial stress on NK cells and HIV progression.
Cytokines
A great deal of research has also been done concerning the balance of cytokines in the immune response. Pro-‐inflammatory cytokines can stimulate inflammation, while anti-‐inflammatory cytokines can inhibit inflammation
(Gleeson & Bosch, 2013). Interleukin 6 (Il-‐6) is a pro-‐inflammatory cytokine, released in the acute phase of inflammation. IL-‐6 can lead to the worsening of a disease by increasing the activation of the immune system, for instance
producing fever (Gleeson & Bosch, 2013).
It has been demonstrated that HIV infected people have an increased concentration of IL-‐6 (Kinter, Artos, Cicala, & Fauci, 2000). A pioneer study assessed the relationship between chronic stress and Il-‐6 production among 119 men and women who were caregiving for a spouse with dementia
(perceived as a chronic stressor) and 106 non-‐caregivers (Kiecolt-‐Glaser 2003). The results showed that Il-‐6 levels were four times higher in caregivers
compared to non-‐caregivers. It can be implied that there is a relationship between chronic stress and Il-‐6 and dysregulation of the immune system. It is therefore plausible that adverse psychosocial factors can affect IL-‐6 levels, which in turn can stimulate HIV progression.
A number of psychosocial risk factors have been associated with HIV progression, among these strong Type C coping, a chronic psychosocial risk factor (Solano et al., 2002). Type C is a passive coping pattern defined by emotional inexpressiveness, a decreased recognition of one’s own needs and feelings, but with a focus on the needs and feelings of others. Since Type C coping is considered to keep the individual in a chronic state of stress, it is hypothesized that Type C coping is also associated with higher IL-‐6 production, which in turn is associated with increased HIV progression by possibly increasing the
activation of the immune system (Temoshok et al., 2008). In a study of 200 HIV infected patients, it was investigated whether Type C coping assed by a self-‐ report questionnaire would be associated with and increase production of Il-‐6, (assessed 3-‐6 days after). Results showed that Type C coping was associated with increased concentration of IL-‐6. However, the correlational nature of this study does not allow the conclusion that Type C coping leads to the increased concentration of Il-‐6, shifting the balance between pro-‐and anti-‐inflammatory towards the pro-‐inflammatory side, which would possibly explain the
progression in HIV.
Adverse psychosocial risk factors can also make individuals prone to unhealthy habits, such as poorer sleep quality, drug abuse, poorer nutrition and
less exercise, which are also related to high IL-‐6 concentrations (Ader, Felton & Cohen, 2000). A study by Fumaz et al. (2012) therefore collected information about health-‐related variables to control their possible contribution to the relationship of psychological stress and IL-‐6 levels. Fifty subjects participated in the study, during which the researchers assessed psychological stress, anxiety and depression as well as health behaviours with self-‐report questionnaires. CD4+ cell count, viral load, and Il-‐6 were measured with a blood sample. In their study, perceived psychological distress, anxiety and depression among HIV infected individuals as well as a healthy diet (Mediterranean diet) and adherence were associated with higher levels of circulating IL-‐6. Among all the variables assessed together (diet, exercise, sleep quality, smoking, sexual risk intercourse, drug intake), psychological distress and adherence were the only variable which remained strongly associated with levels of IL-‐6. These results imply that there is an association between episodic psychosocial factors, IL-‐6, and HIV progression. In conclusion, it has been shown that episodic and chronic psychosocial risk factors are related to increased IL-‐6 levels, as well as HIV disease
progression. To get a better picture of the actual causal relationship between these psychosocial risk factors and HIV disease progression, and whether immune mechanism could function as a mediator, experimental studies are needed.
Conclusion and Discussion
This thesis has explored the biological pathways (HPA axis, SNS, and immune mechanism) that underlie the relationship between adverse psychosocial factors and HIV disease progression. The first question of whether the HPA axis (the release of cortisol) mediates the relationship between psychosocial factors and HIV disease progression, was not answered in this thesis. Furthermore, findings were inconsistent with regards to whether there is a relationship of any kind between cortisol and HIV disease outcome. Concerning the SNS, however, this review gives consistent evidence (from observational studies, in vitro studies and experimental animal models) indicating that there is an association between
psychological stress (episodic and chronic), HIV disease progression and increased SNS activity. Moreover, there is evidence that in animals heightened SNS activity mediates the influence of psychosocial risk factors on HIV disease progression. Third, it was discussed whether immune mechanisms, in particular NK cell and the IL-‐6 cytokine, could act as a possible mediator of the relationship between adverse psychosocial factors and HIV disease severity. Concerning NK cells there is evidence that episodic psychosocial stress factors are related to lower NK cell responsiveness. Moreover, acute stress was related to increases in NK cell number. This supports the bidirectional theory of stress, which states that acute stress is immune-‐enhancing, while prolonged exposure to stress is immunosuppressive. Furthermore, it can be concluded that episodic and chronic psychosocial risk factors are related to increased IL-‐6 levels, as well as HIV disease progression. Finally, all studies support the previously found results by Chida and Vedhara (2009) that episodic and chronic adverse psychosocial factors are associated with accelerated HIV progression.
However, all these results have to be analyzed with caution. In general, most of the data comes from observational studies; a causal direction of the relationship is therefore not examined. Whether different activation in these pathways (immunological, HPA and SNS) represents a consequence of prolonged stress or causes it as well as a causes of HIV disease progression, or is a
consequence of it, is therefore not fully proven. In some studies, experimental animal models or interventions have been used to examine this relationship and it seemed likely that prolonged stress causes changes in these pathways which in turn causes accelerated disease progression (Antoni et al., 2005; Sloan et al., 2006). However, more and rigorously designed experimental studies where researchers can randomly assign individuals to interventions, which alter psychosocial circumstances, or animals to different environmental conditions, are needed to lend further credence to the existence of a causal relationship between adverse psychosocial factors and HIV disease progression.
Furthermore, it is also plausible that adverse psychological factors affect HIV progression through health behavior pathways (exercise, diet, substance use, sleep quality, adherence, and exposure to sexually transmitted infections). Research has demonstrated that depressed mood and stressful days per year are
related to an extremely high body mass index, lower physical activity, high alcohol use and smoking (Kobau et al., 2004). Smokers for example had poorer viral responses to their medication (Feldman et al., 2006), and it has been demonstrated in vitro that alcohol may supress the immune system in HIV (Wang et al, 2002). Above all, adherence is a very important factor in successful HIV treatment, lower adherence rates will result in health complications and HIV progression (Kiecolt-‐Glaser, Robles, & Glaser, 2002). Adverse psychosocial factors, such as depression are associated with poor adherence to HAART and with increased morbidity (Perry & Karasic, 2002). Even though health
behaviours are not sufficient to explain the relationship between adverse psychosocial factors and HIV disease progression (Kiecolt-‐Glaser et al., 2002), future research is required, which examines the multidirectional pathways, such as physiological and behavioural mediators of the association between adverse psychosocial factors and HIV disease progression.
Confounding variables, such as health behaviours, demographic variables and medication intake (as SSRI) have to be controlled for more thoroughly to isolate the effect psychosocial factors have on biological pathways. SSRI, for example, which is most likely being taken by a part of the participants in these studies, might have an effect on inflammatory responses (O’Conner et al., 2009). Moreover, it has been demonstrated that exercise is related to the Il-‐6 level (Plaisance & Grandjean, 2006). It is therefore recommended that researchers should ask participants in the studies where IL-‐6 is measured, not to exercise on the day of the research. Another example is adherence to ART, which plays a significant role in disease outcome, and is therefore essential to be controlled for thoroughly. Other variables such as body mass index (BMI), diet, alcohol use, caffeine, smoking, sleep disturbance, socioeconomic status, should also be
obtained. If it is not possible to create group-‐conditions, which are comparable in these terms, variations in these variables should at least be controlled for
statistically.
Generally, this review provided a step forward to a better understanding of the underlying mechanisms linking adverse psychosocial factors to HIV disease progression. Given the evidence suggesting that adverse psychosocial factors are related to biological markers, and HIV disease outcome, it might be
clinically relevant to assess the level of stress and depression as well as biological markers, such as epinephrine en cortisol, in patients starting
antiretroviral medications. The evidence provided by this review should inspire future research to examine the effect of psychological interventions as well as pharmacological treatments on adverse psychosocial factors and biological markers to see if altering these variables may lead to a positive change in health status. Furthermore, other common diseases should be examined, such as the effect of adverse psychosocial factors on cancer, on diabetes, or on allergies. For now, the knowledge gained will lead us a step further down the path to creating better treatment options for HIV-‐positive persons, which could enhance physical and psychological health status, so that the 35 millions of people infected with HIV can improve their life quality immensely.
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