Progressive dysregulation of autonomic and HPA axis functions in HIV-1 clade C infection in South India

Abstract

Human immunodeficiency virus type 1 (HIV-1) infection causes a wide spectrum of abnormalities in neurological, neuropsychological, and neuroendocrinological functions. Several studies report disturbance in autonomic nervous system (ANS) and hypothalamic pituitary-adrenal (HPA) axis function in HIV-1B infected individuals. However, no such investigations on the effect of HIV-1 clade C infection, particularly during the initial phase of the disease progression, have been reported. The present investigations were carried out longitudinally over a 2-year period at 12 monthly intervals in clinically asymptomatic HIV-1 clade C seropositive patients (n=120) and seronegative control subjects (n=29). We determined both the basal levels and the dynamic changes in plasma levels of norepinephrine (NE), epinephrine (E), adrenocorticotrophic hormone (ACTH) and cortisol (CORT). Studies were also extended longitudinally (at three separate yearly visits of each participant), to evaluate the response of autonomic and HPA axis to mirror star tracing challenge test (MSTCT) and the values were determined as area under the curve (AUC, corrected for baseline levels of NE, E, ACTH, and CORT). The findings show that the values of basal plasma NE levels, as well as NE response to MSTCT (AUC) at the first visit of HIV-1 seropositive individuals did not differ from those found in the control subjects (NE, pg/ml, HIV-1C=313.5+/-12.7 vs. controls=353.0+/-21.3; p=NS; AUC, HIV-1C=225+/-14.75 vs. controls=232.7+/-19.34; p=NS, respectively). At the subsequent two visits of HIV-1 positive patients however, NE response to MSTCT challenge was progressively attenuated (AUC=235+/-19.5 and 162.7+/-13.6; p<0.01 and 0.05, respectively) compared to that found at the first visit. On the other hand, plasma levels of E as well as E response to MSTCT at the first visit were significantly lower in HIV-1C seropositive individuals compared to those in the control subjects (pg/ml, HIV-1C=77.30+/-5.7 vs. controls=119.1+10.5; p<0.05; AUC, HIV-1C =83.29+/-7.5 vs. controls=172.3+/-18.9; p<0.001), but no further change was observed in AUC of E in response to MSTCT at the two subsequent yearly visits. The basal plasma levels of ACTH in HIV-1C seropositives were not different than in the control subjects (pg/ml: HIV-1C=20.0+/-0.9 vs. controls=23.1+/-1.6; p=NS), but ACTH response to MSTCT in HIV-1C seropositive patients at the first visit was lower than in the controls (AUC, HIV-1C=23.57+/-1.5 vs. controls=30.94+/-3.5; p<0.05), and fluctuated between high and low at the second and third visits (AUC, 28.89+/-2.3 and 21.69+/-2.36, respectively). However, the baseline plasma levels of cortisol as well as the response of cortisol to MSTCT (AUC) in HIV-1C seropositive individuals were higher than in the control subjects at the first visit (mug/dl, HIV-1C=9.83+/-0.39 vs. controls=6.3+/-0.56; p<0.05; AUC, HIV-1C=12.31+/-0.7 vs. control=9.18+/-0.9; p<0.05), and remained high at the two subsequent yearly follow up visits of HIV-1C (AUC, 11.8+/-0.86 and 11.98+/-0.77, respectively). These findings demonstrate attenuated autonomic functions, a disconnection between response of ACTH and cortisol to the MSTCT challenge, and an inverse relationship between plasma levels of catecholamine(s) and cortisol. Since plasma catecholamines and cortisol are the peripheral mediators of the autonomic and HPA axis function, the findings of this study reflect the overall adverse effect of HIV-1C infection on autonomic as well as HPA axis functions. The findings, apart from being the first to demonstrate the progressive dysregulation of autonomic nervous system and HPA axis function among HIV-1C infected seropositive individuals much ahead of the onset of acquired immunodeficiency syndrome (AIDS), also suggest that MSTCT, involving visuoconstructive cognitive abilities, is an effective stressor for unraveling the underlying dysfunctions in the neuroendocrine functions in health and disease.