Adrenal function has long been known to have a powerful influence on the immune system, but it has only recently become apparent that the immune system, in turn, can modulate the hypothalamic- pituitary-adrenal (HPA) axis. The physiology of this two-way relationship is incompletely understood, and even less known about its pathophysiology in disease states. Since infection with the human immunodeficiency virus (HIV) can profoundly affect the immune system and is also associated with adrenal insufficiency, HIV provides an important opportunity to investigate the putative immune-adrenal axis. It is possible, that abnormalities in the immune-adrenal axis in HIV infection may lead to activation of latent infection, worsening of already manifest disease, stimulation of autoimmune phenomenon, or acquisition of an opportunistic infection. The present proposal will, therefore, study the interrelationship of the immune-adrenal system subjects infected with HIV. These subjects will be recruited from the Boston City hospital AIDS clinic. They will undergo a five-day testing protocol to assess HPA reserve, with an insulin tolerance test, CRH stimulation test, and short and long ACTH stimulation tests. In parallel with these studies, mononuclear leukocytes will be harvested to assess their production or cytokines which can stimulate the HPA axis (adrenotropic) immune function. These cells will be collected and stained for the production of POMC peptides including ACTH1-13. These cells will be cultured (24 hours) and the supernatants will be tested for adrenotropic activity in a rat bioassay, pituitary cell culture, and dispersed adrenal cell incubation assay. After these studies, the subjects will be followed longitudinally, with yearly testing or repeat testing if the HIV disease progresses, which ever occurs first. Data from these studies will quantify the frequency and severity of abnormal adrenal function, and if present whether this is due to hypothalamic, pituitary, adrenal or immune-related causes. Following initial studies, HIV-infected subjects will be rested yearly. Longitudinal data will assess whether defects in the immune-adrenal axis are related to either activation of latent HIV infection or worsening of already manifest HIV or opportunistic infection.
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