The overall goal of this proposal is to pursue our initial findings of the deleterious effects of stress on immunity and disease progression in HIV infection. The present application provides a rare opportunity to address an unanswered question of great popular and scientific concern - """"""""Does stress influence the course and outcome of physical diseases such as cancer and HIV infection?"""""""" Findings from the initial study period provide the first clear evidence that stress is not only predictive of early HIV disease progression but also is associated with alterations in immunity, suggesting that stress influences disease progression by altering key parameters of cellular immunity. Thus, these data provide the first evidence from a prospective study employing longitudinal, repeated assessment of stress, immunity, and disease progression that stress produces clinically relevant alterations in an immune-based disease. The rationale as well as the importance of these findings is based on several factors: I) although there is popular enthusiasm for the concept that stress influences the course of physical illness, there is no compelling scientific evidence to support this view; 2) although considerable evidence suggests that both stress and depression are associated with alterations in immunity there are no data establishing the clinical relevance of these associations; 3) although there is evidence that stress increases the likelihood of recurrence of breast cancer and that stress intervention is associated with increased survival in breast cancer, no study has assessed the underlying role of immune mediation; 4) although there is positive and negative evidence that depressive symptoms influence HIV disease progression these studies have not assessed stress and are associated with significant drawbacks. In this competitive renewal, we will address methodological limitations of previous studies by continuing our evaluation of this cohort in a more streamlined, longitudinal study, that will permit assessment of the effects of stress and depression on the later progression of HIV infection. Using a prospective design, the proposed studies will test the hypotheses that stressful life events and associated depressive symptoms are predictive co-factors of HIV disease progression, and that these effects on disease progression are mediated by changes in immunity. We believe it is imperative to extend this study because we have a unique opportunity to determine the effect of stress on early and advanced disease progression and ultimately mortality. The proposed studies are designed to: 1) establish a definite relationship between stress and later HIV disease progression: 2) begin to determine whether important changes in host defense (e.g., killer cell levels and their functional activity) correlate with stress-associated changes in clinical status. and 3) determine if alterations in glucocorticoid function correlate with changes in immune/disease status. Thus, while our goal is to ultimately understand causal mechanisms linking stress, immune function and HIV illness, the proposed studies are critical to first establish a definite association between stress and immune-based illness. Without such information, it will not be possible to design rationale studies to elucidate causal mechanisms. Once these observations are soundly established, then it will be feasible to examine potential causal mechanisms at the physiological cellular and molecular levels.
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