Personality and serotonin transporter genotype interact with social context to affect immunity and viral set-point in simian immunodeficiency virus disease

Abstract

From the beginning of the AIDS epidemic, stress has been a suspected contributor to the wide variation seen in disease progression, and some evidence supports this idea. Not all individuals respond to a stressor in the same way, however, and little is known about the biological mechanisms by which variations in individuals’ responses to their environment affect disease-relevant immunologic processes. Using the simian immunodeficiency virus/rhesus macaque model of AIDS, we explored how personality (Sociability) and genotype (serotonin transporter promoter) independently interact with social context (Stable or Unstable social conditions) to influence behavioral expression, plasma cortisol concentrations, SIV-specific IgG, and expression of genes associated with Type I interferon early in infection. SIV viral RNA set-point was strongly and negatively correlated with survival as expected. Set-point was also associated with expression of interferon-stimulated genes, with CXCR3 expression, and with SIV-specific IgG titers. Poorer immune responses, in turn, were associated with display of sustained aggression and submission. Personality and genotype acted independently as well as in interaction with social condition to affect behavioral responses. Together, the data support an “interactionist” perspective [Eysenck, H.J., 1991. Personality, stress and disease: an interactionist perspective. Psychol. Inquiry 2, 221–232] on disease. Given that an important goal of HIV treatment is to maintain viral set-point as low as possible, our data suggest that supplementing anti-retroviral therapy with behavioral or pharmacologic modulation of other aspects of an organism’s functioning might prolong survival, particularly among individuals living under conditions of threat or uncertainty.

Introduction

From early in the AIDS pandemic, psychosocial stress has been proposed as a contributor to the wide variation seen in the rate of HIV disease progression (Coates et al., 1984). Research has shown that the experience of stressors such as bereavement (Kemeny and Dean, 1995) and other negative life events (Leserman et al., 2002) are associated with indicators of more rapid disease progression in humans. Using the simian immunodeficiency virus (SIV)/rhesus macaque model of AIDS, we have demonstrated experimentally (Capitanio et al., 1998) and with a large archival cohort (Capitanio and Lerche, 1998) that social stress is associated with shorter survival in monkeys infected with SIV.

Not all individuals are affected equally by challenging circumstances, however; variation in individual traits has also been related to disease outcome. For example, Leserman et al. (2000) showed that HIV+ gay men who cope with stressful circumstances by using denial displayed an accelerated disease course, and Cole et al. (1997) found that individual differences in social sensitivity moderated the relationship between exposure to social rejection and disease progression in HIV+ gay men. An exploratory analysis of SIV-infected rhesus monkeys (Capitanio et al., 1999) suggested that the personality trait Sociability may be a relevant moderating factor when stressors are social in nature. Sociability is a commonly found personality dimension in non-human primates (Capitanio, 2004) and is akin to Extraversion in humans (Gosling and John, 1999). In rhesus monkeys, High-Sociable (HS) animals show higher frequencies of affiliation, greater sensitivity to social cues, and a greater tetanus-specific IgG response following social change compared to Low-Sociable (LS) animals (Capitanio, 1999, Capitanio, 2002, Maninger et al., 2003). Our earlier analysis (Capitanio et al., 1999) suggested that LS animals may be at greater risk for faster disease progression than are HS animals. Together, these and other studies suggest that, while stress may exert a main effect on disease progression, variation in psychosocial traits may moderate the host’s response to stress and affect disease course.

In stressful circumstances, an individual’s psychological functioning and the progress of disease may also be affected by factors that are not explicitly psychosocial. In the psychiatric literature, attention has focused on how candidate genes associated with brain monoaminergic activity, such as the serotonin (5-HT) transporter gene-linked polymorphic region (5-HTTLPR), are related to psychological characteristics such as aggressiveness, anxiety, neuroticism, etc. The serotonin transporter gene codes for a protein responsible for the presynaptic uptake of serotonin following neuronal release. The promoter is biallelic in rhesus monkeys and humans, with the short allele leading to reduced expression of the transporter protein. Both human and non-human primate evidence indicates that individuals possessing a short allele are more likely to display aggression and/or anxiety, particularly under adverse conditions (Lesch et al., 1997, Barr et al., 2003, Holmes et al., 2003, Caspi and Moffitt, 2006). While we are not aware of any studies evaluating the role of such genes in infectious disease, given the association between aggression/anxiety and disease processes (e.g., Moller et al., 1999, Zorilla et al., 1994), candidate genes such as these may have an important moderating influence.

Presumably, the influence of personality and genotype on disease processes will be mediated through their effects on physiological stress-response systems. In the context of HIV/SIV disease, there is some evidence that the sympathetic nervous system can affect disease course. In vitro work has shown that catecholamines associated with the sympathetic nervous system can accelerate HIV-1 replication (Cole et al., 1998) and Sloan et al. (2006) have demonstrated that SIV replicates at increased frequency in the vicinity of catecholaminergic varicosities in lymph nodes. Other research suggests that hypothalamic–pituitary–adrenal (HPA) function is associated with variation in the course of HIV/SIV disease (Leserman et al., 2000, Leserman et al., 2002). Our animal model of social stress, for example, found reduced basal cortisol, and evidence of enhanced negative feedback, in monkeys that experienced stressful social conditions. These animals ultimately showed significantly shorter survival (Capitanio et al., 1998). In the current study, we focused on plasma cortisol concentration as a possible physiological mediator of host characteristics on immune and viral outcome measures.

The present research was undertaken to explore some mechanisms by which “person by situation” interactions affect SIV disease progression. Our principal measure of disease progression was viral RNA (vRNA) copy number measured at Week 10 post-inoculation (p.i.). By approximately 6 weeks p.i., vRNA levels typically stabilize (Staprans et al., 1999) around a “set-point” that reflects the ability of the immune system to regulate viral production. Viral set-point remains relatively stable over the course of disease until progression to AIDS. Remarkably, variation in set-point measured early in disease correlates very highly with survival. In our earlier study of SIV-infected rhesus monkeys (Capitanio et al., 1998), vRNA levels at Week 10 p.i. correlated −0.79 with survival. Comparably strong effects have been found by others for both SIV (e.g., Watson et al., 1997) and HIV (e.g., Mellors et al., 1996).

The strong correlation between early vRNA set-point and survival suggests that events early in infection are critically important to the progress of the disease. Recent work using the SIV/rhesus macaque model, for example, has shown the surprising impact of the virus on host defenses within the first few weeks of infection (e.g., Mattapallil et al., 2005, Li et al., 2005), and increased attention has focused on mechanisms associated with innate immunity (Levy et al., 2003, Ahmed et al., 2005). In general, the first line of defense against viral infection is the interferon system. Type I-interferons (IFNs) such as IFN-α are produced by virally infected cells at high levels within hours of infection. IFNs up-regulate transcription of effector proteins (such as Mx and OAS [2′-5′ oligoadenylate synthetase]), and together the interferon system can act in an autocrine and paracrine fashion to inhibit protein synthesis and induce an anti-viral state. IFNs also activate NK cells, which produce and secrete the Type II interferon, IFN-γ, and its effector molecules, such as CXCL9. Interferons can also affect adaptive immune responses (Biron, 1998). The role of interferon systems in HIV/SIV infection is not straightforward, however. On the one hand, a reduction in the number of circulating cells that produce Type I interferons is associated with progression (e.g., Soumelis et al., 2001). On the other hand, studies with SIV-infected monkeys have demonstrated that Type I interferon responses during acute SIV infection are ineffective in controlling viral replication (Abel et al., 2002), presumably because HIV can block the effector functions of interferon-induced proteins (e.g., Sen, 2001).

We had several goals for the present study. First, we wanted to confirm whether viral set-point is associated with survival as we and others have demonstrated. Second, because there is relatively little information on innate immune responses early in immunodeficiency virus infection, we wanted to describe how such measures change during early SIV infection, and then to identify which of these measures is associated with variation in vRNA. Our third and principal goal was to determine whether Sociability and serotonin transporter genotype interact with social condition to affect behavior, and how the behavioral responses were associated with the immune changes that were predictive of vRNA. We had several specific predictions: we expected that social stress would be associated with a poorer SIV-specific IgG response, which would confirm an earlier report from our laboratory (Capitanio et al., 1998); and we expected that animals in Unstable (but not in Stable) social conditions that were Low-Sociable, and animals in Unstable (but not in Stable) social conditions that possessed a short allele for the rhesus 5-HTTLPR (rh5-HTTLPR) would be most likely to (1) experience sustained agonistic behavior, resulting in (2) altered cortisol concentrations and changes in Type I interferon responses that would be associated with (3) higher vRNA. Our model for these relationships is illustrated in Fig. 1, which also shows the specific conditions and variables that were examined in the present study.