PSYCHOLOGICAL STRESSORS AND HIV/AIDS

Animal literature has indicated that stressors accelerate HIV pathogenesis. For example, rhesus macaques assigned to stable or unstable social conditions and inoculated with the simian immunodeficiency virus have different outcomes. Animals in the unstable condition displayed more agonism and less affiliation, shorter survival and lower basal concentrations of plasma cortisol [5]. Early after inoculation, but before the emergence of group differences in cortisol levels, animals receiving social threats had higher concentrations of simian immunodeficiency virus RNA in plasma, and those engaging in affiliation had lower concentrations.

Human studies confirm these findings. In her review of the literature, Leserman [6] found substantial and consistent evidence that chronic depression, stressful events and trauma may accelerate HIV disease progression in terms of decreases in CD4 T lymphocytes, increases in viral load and greater risk for clinical decline and mortality. For example, in an early study of HIV-infected men who have sex with men (MSM), those who had experienced an AIDS-related bereavement event showed a more rapid decline in CD4+ count during follow-up [7]. Conversely, men who found meaning after an AIDS-related bereavement demonstrated less rapid declines in CD4 count and lower rates of AIDS-related mortality [8].

A 9-year follow-up study of MSM living with HIV found that stressful life events were associated with adverse immunological and health effects [9]. Furthermore, higher cumulative-average stressful event score was predictive of faster progression to AIDS (decline in CD4+ T lymphocytes <200 and/or AIDS indicator condition). Similarly, the CHASE (Coping with HIV/AIDS in the Southeast) study found that individuals with more categories of lifetime trauma had faster all-cause and AIDS-related mortality [10], and that trauma was associated with faster development of an opportunistic infection or AIDS-related death [11].

A range of other studies confirm these kinds of findings. HIV-infected individuals with more life events had greater increases in viral load during a 2-year follow-up [12]. More than one negative life event was associated with almost a threefold increased risk of immune suppression in a 1-year study of HIV-infected children and youth [13]. Amongst women who reported a traumatic event, those who also met the criteria for post-traumatic stress disorder (PTSD), demonstrated a lower CD4 to CD8 ratio during 1-year follow-up of asymptomatic HIV-infected African American women [14].

Although not all studies are consistent, those with short follow-up periods, only baseline stress measures and/or self-rating methods to assess life stress may be less likely to show an association of stress with reduction in CD4+ T lymphocyte counts or HIV disease progression [6]. The most consistent findings on health impact of stress and trauma in HIV come from studies using interview-based stress ratings measured over time or from studies of major lifetime trauma [6]. It is possible that traumatic events continue to exert effects over long periods of time, whereas stressful events (e.g. change in employment, relationship break-up) have greater impact if cumulative [6]. A range of other adverse psychosocial factors may also be important [15–17].

Furthermore, stressors may impair the impact of antiretroviral (ARV) treatment. Cole and colleagues [18] found that HIV-positive individuals with high levels of autonomic nervous system (ANS) activity experienced poorer suppression of plasma viral load and poorer CD4+ T cell recovery over 3–11 months of treatment with ARVs, consistent with the hypothesis that ANS neural activity directly promotes residual viral replication. Whilst it has been suggested that the effects of stressors are due to poor adherence to ARV or retention in care [19, 20], there is also evidence that the effects of stressors are apparent even when adherence is controlled for [21].

PSYCHOBIOLOGY OF THE STRESS RESPONSE

The neurobiology of the stress response and of PTSD has been a growing area of research [22]. There is evidence that stressors and PTSD lead to alterations in cognitive-affective functioning, which are in turn underpinned by specific changes in neuronal circuitry, and ultimately by alterations in component neurotransmitters, neuroendocrine pathways (e.g. the hypothalamic–pituitary–adrenal (HPA) axis) and other molecules [23]. Nevertheless, relatively little work has specifically explored the molecular mechanisms involved in the stress response or PTSD in HIV/AIDS.

Given the evidence that patients living with HIV who experience maladaptive grief show more rapid losses of CD4 T-cells over time [21], a number of early studies focused on HIV men who had lost a partner. Such research found that bereaved men with HIV had a significant increase in immune activation (e.g. increased serum neopterin) and a significant decrease in the lymphocyte proliferative response to phytohaemagglutinin [24, 25]. Additional molecular work on HIV populations facing specific psychological traumas and stressors may well be useful.

It is notable that neurons from the sympathetic division of the ANS terminate in the parenchyma of lymphoid organs and release norepinephrine into T-cell-rich compartments. Furthermore, cellular β2 adrenoreceptors modulate leukocyte activation, localization and cytokine production via GαS protein-mediated induction of cAMP/protein kinase A (PKA) signalling. Indeed, Cole et al. [18] found that the ANS neurotransmitter norepinephrine enhanced replication of HIV-1 in vitro via chemokine receptor upregulation and enhanced viral gene expression, suggesting that neural activity may directly promote residual viral replication.

Indeed, Cole [4] argued that given that somatic nervous system (SNS) and HPA effector molecules can enhance HIV-1 replication via effects on viral infectivity, viral gene expression and the innate immune response, the regulation of leukocyte biology by such molecules provides a plausible biological model of how psychological factors influence the course of HIV disease. Further work is, however, required to integrate the growing psychobiology of stress and PTSD with more recent work on HIV psychoneuroimmunology [26]. There is scope for such work to be translational in nature and to include both genetic and environmental factors [27].