Abstract
Purpose: Increased incidence of depression in HIV+ patients is associated with lower adherence to treatment and increased morbidity/mortality. One possible underlying pathophysiology is serotonergic dysfunction. In this study, we used an animal model of HIV, the SIV-infected macaque, to longitudinally image serotonin transporter (SERT) expression before and after inoculation, using 11C-DASB (SERT ligand) PET imaging. Methods: We infected seven rhesus macaques with a neurovirulent SIV strain and imaged them at baseline and multiple time points after inoculation (group A). Pyrosequencing methylation analysis of the SERT promoter region was performed. We also measured SERT mRNA/protein in brain single-cell suspensions from another group (group B) of SIV-infected animals (n = 13). Results: Despite some animals showing early fluctuations, 86% of our group A animals eventually showed a net increase in midbrain/thalamus binding potential (BPND) over the course of their disease (mean increased binding between last time point and baseline = 30.2% and 32.2%, respectively). Repeated-measures mixed-model analysis showed infection duration to be predictive of midbrain BPND (p = 0.039). Thalamic BPND was statistically significantly associated with multiple CSF cytokines (P < 0.05). There was higher SERT protein levels in the second group (group B) of SIV-infected animals with SIV encephalitis (SIVE) compared to those without SIVE (p = 0.014). There were no longitudinal changes in SERT gene promoter region percentage methylation between baselines and last time points in group A animals. Conclusion: Upregulated SERT leading to lower synaptic levels of serotonin is a possible mechanism of depression in HIV+ patients, and extrapolating our conclusions from SIV to HIV should be sought using translational human studies.
Highlights
Despite mounting evidence of higher depression rates in HIVpositive (HIV+) individuals compared to seronegative controls and associated increased morbidity and mortality [1], there is limited literature targeting the underlying mechanisms of depressive disorders in HIV
The study was approved by the Animal Care and Use Committee of the National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)
Mean binding potential normalized to non-displaceable tissue radioligand (BPND) values in the selected Volumes of interest (VOIs) were highest in the midbrain, followed by the thalamus, caudate/putamen, and cerebellum, which is similar to reported postmortem serotonin transporter (SERT) densities [25]
Summary
Despite mounting evidence of higher depression rates in HIVpositive (HIV+) individuals compared to seronegative controls and associated increased morbidity and mortality [1], there is limited literature targeting the underlying mechanisms of depressive disorders in HIV. Disruption of cytoskeletal genes and dysregulation of somatostatin were found to be part of the pathologic process of major depressive disorder (MDD) in the setting of HIV [3]. The only previous positron emission tomography (PET) study targeting SERT in the setting of HIV depression demonstrated generally lower 11C-DASB (radioactive ligand targeting SERT) binding in HIV+ patients compared to healthy controls. Depressed HIV+ patients, showed higher 11C-DASB binding than non-depressed patients, suggesting SERT upregulation in the depressed group and possible abnormal serotonergic transmission in HIV-associated depression [6]. No other similar cross-sectional or longitudinal PET studies have been performed to date
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