HORMONES 2008, 7(3):205-216 Review Dysfunction of the Hypothalamic-Pituitary-Adrenal axis in HIV infection and disease Evangelia Zapanti1, Konstantinos Terzidis1, George Chrousos2 11st Department of Endocrinology, “Alexandra” Hospital, Athens, 2Endocrine Unit, Department of Pediatrics, Athens University School of Medicine, “Aghia Sophia” Children’s Hospital, Athens, Greece ABSTRACT Abnormalities of the Hypothalamic-Pituitary-Adrenal (HPA) axis have been documented in HIV patients in the early as well as late stages of the infection and range from subtle subclini- cal disturbances to frank adrenal insufficiency. Potential etiologies of these disorders include opportunistic infections, neoplasms, drugs administered to treat infections, cytokine abnor- malities associated with the HIV disease process and acquired alterations in tissue sensitivity to glucocorticoids. In this article, we present a concise review of HPA abnormalities in HIV infection and disease with regard to their etiology with emphasis on syndromes of hypersen- sitivity/resistance to glucocorticoids associated with antiviral medications and/or the HIV infection itself. Key words: AIDS, Glucocorticoid hypersensitivity, Glucocorticoid resistance, HIV, HPA axis, Vpr INTRODUCTION peptide that plays a central role in coordinating the HPA axis and the systemic response to stress,3 act- HPA axis ing as the main physiologic ACTH stimulus.4 ACTH The HPA axis and the systemic sympathetic/ad- leads to secretion of cortisol (F) and other adrenal renomedullary (sympathoadrenal) system are the steroids, such as dehydroepiandrosterone (DHEA) peripheral branches of the stress system, whose main and aldosterone.5 function is to maintain basal and stress-related ho- meostasis.1 Biologic, physical or psychologic stimuli The HPA axis and the immune-inflammatory activate the stress system, including the HPA axis. Such response activation has been referred to as stress response.2 Complex interactions exist between the HPA axis The primary mediator of this response is cortico- and the immune system.1,6,7 Several inflammatory tropin-releasing hormone (CRH), a 41-amino acid signals, mainly consisting of circulating cytokines, are produced as a result of innate and adaptive immune Address for correspondence: system activation. These cytokines play a major role Evangelia Zapanti, 8 S. Karageorga Str., 166 75 Glyfada, in the protection of the organism from foreign attacks Greece, e-mail: [email protected] and in the pathogenesis of autoimmune processes,8 Received 27-06-07, Revised 30-03-08, Accepted 20-04-08 accounting for most of HPA axis activation dur- 206 E. ZAPANTI ET AL ing an ongoing infectious or inflammatory disease. of cortisol associated with blunted responsiveness to Among them, tumor necrosis factor-alpha (TNF-α), cosyntropin were also reported.20 The significance of interleukin (IL)-1 and IL-6 activate the HPA axis such blunted responses is not clear. Evaluation of the independently, albeit in a synergistic way.9 HPA axis with CRH test in patients with early HIV infection who had normal responses to cosyntropin re- In addition to their effects on the hypothalamus, vealed reduced cortisol responsiveness,19,20 suggesting cytokines can stimulate ACTH and cortisol release that many asymptomatic patients in the early stages of by acting directly on the pituitary and adrenals, re- the disease may have subclinical primary or second- spectively.10,11 Other inflammatory mediators, like ary adrenal insufficiency. The low responsiveness of interferon-α, interferon-γ, interleukin-2, epidermal the pituitary to CRH was attributed to a reversible growth factor (EGF), transforming growth factor-β effect of cytokines.13 In a study of 25 asymptomatic (TGF-β) and platelet activating factor (PAF), may HIV patients, normal adrenal capacity was reported; also participate in the regulation of the HPA axis, however, 32% had elevated plasma ACTH at the directly or indirectly, by stimulating the release of two-year follow-up, suggesting a progressively com- inflammatory cytokines.1,3 promised adrenal reserve.21 With progression towards Activation of the HPA axis and hence the release AIDS, overt adrenal insufficiency may be established of glucocorticoids has a pivotal role in adaptation dur- in some patients, often secondary. However, in AIDS ing the stress of infection by modulating the immune patients, adrenal function is rarely compromised and inflammatory response. Glucocorticoids suppress the adrenal insufficiency observed in some of them immune activation of inflammatory cells, inhibit can be attributed to specific causes, such as adrenal the production of cytokines (TNF-α, IL-1β, IL-6) or pituitary infection or neoplastic infiltration, and and other inflammatory mediators1,3 and suppress is associated with the typical biochemical features of certain subgroups of lymphocytes, namely Th1 lym- Addison’s disease. phocytes.1,3 Certain cytokines (IL-2, IL-4) can induce resistance to glucocorticoids by decreasing the affinity PATHOGENETIC MECHANISMS OF HPA AXIS 12 of the glucocorticoid receptor to its ligand. In HIV DYSFUNCTION IN HIV PATIENTS infection and disease, cytokines have a central role in activating the HPA axis and thus in the regulation Hypercortisolemia in AIDS patients of the immune response (Figure 1). In a considerable number of AIDS patients, ele- vated basal cortisol levels have been observed.19 HPA FUNCTION IN HIV PATIENTS This might be due to a chronic stress-related shift of steroid production from adrenal androgens toward The HPA axis has been examined extensively in cortisol. Another possible explanation is the increasing AIDS and HIV-infected patients. High13,14 or nor- plasma concentrations of cortisol-binding globulin mal15,16 basal cortisol levels and high,16,17 low17,18 or (CBG) observed with the progression of the disease.22 normal19 ACTH plasma levels have been reported. High cortisol levels associated with low ACTH levels Evaluation using CRH and/or ACTH has revealed may indicate that in HIV infection, cytokines, such derangement of the HPA axis ranging from sub- as IL-1β and IL-6, directly stimulate the adrenal clinical alterations in cortisol levels to frank adrenal glucocorticoid synthesis pathway.13,18 Concomitant insufficiency, depending on whether the subjects high levels of ACTH and cortisol often observed in were patients in the early or advanced stages of HIV these patients suggest a stimulatory effect of these infection. cytokines on CRH release.23 In addition, more recent In patients with early HIV infection, adrenal data suggest that the HIV envelope protein gp-120 stimulation with ACTH (cosyntropin test) revealed might induce HPA axis hyperactivity.25 Whether the subnormal responses in 8-14% of cases,16,18,19 whereas observed high cortisol levels are beneficial, due to in advanced HIV infection and in AIDS the respective the anti-inflammatory properties of this hormone, rate was 54%.19 Patients with elevated baseline levels or deleterious, as a result of its immunosuppressive HPA axis in HIV infection and disease 207 Figure 1. Schematic representation of HIV-1 effects on the HPA axis. HIV-1 stimulates glucocorticoid action by increasing glucocorticoid sensitivity through the direct effect of Vpr in target tissues. HIV-1 envelope protein gp120 induces glucocorticoid secretion by direct stimulation of the HPA axis. Interleukins-1 and -6 have a stimulatory effect on glucocorticoid secretion both directly by inducing secretion via the adrenal cortex and indirectly by activating CRH and ACTH secretion. A specific subset of patients exhibits glucocorticoid resistant-like phenotype probably attributable to the effects of interleukins IL-2 and IL-4 secreted by infected T cells on glucocorticoid action. properties, remains unclear. However, as in other affinity to its ligand was reduced and the glucocorticoid forms of acute or chronic illness, it might reflect an receptor (GR) number was increased, suggesting a adaptive, albeit allostatic, stress response. partial glucocorticoid resistance state. As mentioned above, this phenomenon might be due to altered Glucocorticoid resistance: cytokine action. A similar glucocorticoid resistance A subset of AIDS patients have clinical manifesta- state is present in glucocorticoid resistant asthma tions indicative of adrenal insufficiency (hypotension, type 2 patients. These patients have a specific cyto- fatigue, skin and mucosal pigmentation) in parallel kine pattern consisting mainly of elevated IL-2 and with a biochemically hyperfunctioning HPA axis IL-4 and also exhibit reduced glucocorticoid affinity characterized by hypercortisolemia and a moderate to its ligand, closely resembling the glucocorticoid increase of ACTH.26 In these patients, glucocorticoid resistance state found in the aforementioned AIDS 208 E. ZAPANTI ET AL patients.27 Another possible explanation for the rela- control subjects. In contrast, the same study demon- tive glucocorticoid resistance of these patients is the strated an intact ovarian androgen responsiveness to increased expression of the GRβ splicing variant of hCG stimulation.37,38 the glucocorticoid receptor relatively to the expres- Influence of altered steroid production on sion of the GRα isoform.28 The GRα isoform is the immune status in AIDS main mediator of glucocorticoid activity and the GRβ isoform is known to inhibit GRα action. Thus, the Plasma DHEA concentrations correlate posi- 39 increased intracellular proportion of GRβ isoform tively with the CD4 cell count. Also, certain