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. 2019 May 23:10:362.
doi: 10.3389/fpsyt.2019.00362. eCollection 2019.

Potential Mechanism for HIV-Associated Depression: Upregulation of Serotonin Transporters in SIV-Infected Macaques Detected by 11C-DASB PET

Swati Shah  1 , Sanhita Sinharay  1 , Kenta Matsuda  2 , William Schreiber-Stainthorp  1 , Siva Muthusamy  1 , Dianne Lee  1 , Paul Wakim  3 , Vanessa Hirsch  2 , Avindra Nath  4 , Michele Di Mascio  5 , Dima A Hammoud  1
Affiliations

Potential Mechanism for HIV-Associated Depression: Upregulation of Serotonin Transporters in SIV-Infected Macaques Detected by 11C-DASB PET

Swati Shah et al. Front Psychiatry. .

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.

Keywords: HIV; PET; SIV; depression; serotonin transporter.

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Figures

Figure 1
Figure 1
Sagittal and axial brain MRI images (A) as well as parametric maps of 11C-DASB BPND at baseline (B) and last time point (C) of SIV #4. Increased BPND can be detected visually at the last time point compared to baseline. Changes in BPND over the course of disease in all seven animals in the midbrain (D) and thalamus (E).
Figure 2
Figure 2
Examples of changes of BPND values at different time points with respect to CSF and plasma VL changes in one fast progressor, SIV #2 (A), and one slow progressor, SIV #5 (B). The green shadow in (A) reflects the duration of antiretroviral treatment.
Figure 3
Figure 3
Change in SERT mRNA levels in PBMCs of infected animals (group A) between baseline and last time point; 50% of the animals showed slight increase in SERT mRNA compared to baseline values.
Figure 4
Figure 4
Western blotting and qPCR results in group B animals (whole-brain lysates). (A) Fold change in protein levels of SIVE compared to non-SIVE animals. (B) Fold change in mRNA expression of SIVE compared to non-SIVE animals. Median and interquartile range values are shown (* = p < 0.05; n.s. = non-significant).
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