Selective serotonin reuptake inhibitor suppression of HIV infectivity and replication

Abstract

Objective: To test the hypothesis that the selective serotonin reuptake inhibitor (SSRI) citalopram would down-regulate human immunodeficiency virus (HIV) infectivity and that the greatest effects would be seen in people with depression. Depression is a risk factor for morbidity and mortality in HIV/acquired immune deficiency syndrome. Serotonin (5-HT) neurotransmission has been implicated in the pathobiology of depression, and pharmacologic therapies for depression target this system. The 5-HT transporter and 5-HT receptors are widely distributed throughout the central nervous and immune systems. Depression has been associated with suppression of natural killer cells and CD8(+) lymphocytes, key regulators of HIV infection.

Methods: Ex vivo models for acute and chronic HIV infection were used to study the effects of citalopram on HIV viral infection and replication in 48 depressed and nondepressed women. For both the acute and chronic infection models, HIV reverse transcriptase activity was measured in the citalopram treatment condition and the control condition.

Results: The SSRI significantly down-regulated the reverse transcriptase response in both the acute and chronic infection models. Specifically, citalopram significantly decreased the acute HIV infectivity of macrophages. Citalopram also significantly decreased HIV viral replication in the latently infected T-cell line and in the latently infected macrophage cell line. There was no difference in down-regulation by depression status.

Conclusions: These studies suggest that an SSRI enhances natural killer/CD8 noncytolytic HIV suppression in HIV/acquired immune deficiency syndrome and decreases HIV viral infectivity of macrophages, ex vivo, suggesting the need for in vivo studies to determine a potential role for agents targeting serotonin in the host defense against HIV.

Figure 1

Effect of SSRI on acute HIV infectivity. For 7-10 days monocyte-derived macrophages (MDM) from HIV-positive women (N=36) were incubated in the presence or absence of the SSRI, citalopram (10^{− 6}mol/L), for 2 h followed by infection with HIV-Bal strain for 4 and 8 days. HIV reverse transcriptase (RT) activity (viral load) was determined. The vertical bars represent the distributions of within subject_differences in HIV RT activity (log 10 scale) at both 4 and 8 days between SSRI-treated MDM culture and untreated cultures.

Figure 2

Effect of SSRI on replication of latent HIV in a chronically infected T-cell line. HIV RT activity (viral load) was determined in chronically infected T-cell cell cultures (24 and 48 hours post-treatment)(N=43) treated with supernatant from PBMCs that in turn were treated with SSRI (treatment) and compared to viral load in chronically infected T-cells treated with supernatant from PBMCs that were not treated with SSRI(control). The vertical bars represent the distributions of within subject_differences in HIV RT activity (log 10 scale) at both 24 and 48 hours between cells in the treatment and control arms.

Figure 3

Effect of SSRI on replication of latent HIV in a chronically infected macrophage cell line. HIV RT activity (viral load) was determined in chronically infected macrophage cell cultures (24 and 48 hours post-treatment)(N=47) treated with supernatant from PBMCs that in turn were treated with SSRI’s (treatment arm) and compared to viral load in chronically infected T-cells treated with supernatant from PBMCs that were not treated with SSRI(control). The vertical bars represent the distributions of within subject_differences in HIV RT activity (log 10 scale) at both 24 and 48 hours between cells in the treatment and control arms.