The Selective Serotonin Reuptake Inhibitor Citalopram Decreases Human Immunodeficiency Virus Receptor and Coreceptor Expression in Immune Cells

Abstract

Background This study investigated whether a selective serotonin reuptake inhibitor (SSRI), citalopram, downregulates the expression of HIV receptor (CD4) and coreceptors (CCR5 and CXCR4) on peripheral blood mononuclear cells (PBMC) and macrophages ex vivo as a potential mechanism of reducing susceptibility to HIV infection. Methods The sample included 150 participants ages 18–58 (59% women, 65% African American, 61% depressed). Monocyte depleted PBMC were treated with phytohemagglutinin (PHA) for 72-hours and then cultured in the presence of IL-2 with vehicle control or SSRI (10−6 M) for 2-hours. To generate monocyte derived macrophages (MDM), monocytes were cultured for 7-days, after which either vehicle control or SSRI (10−6 M) was added for 2-hours. RNA was then collected from both cell types, and CD4, CCR5 and CXCR4 mRNA expression was measured by real-time PCR. Results In PBMC, SSRI treatment decreased expression of CD4 (p=.009), CCR5 (p=.008), and CXCR4 (p<.0001). In MDM, SSRI decreased expression of CD4 (p<.0001) and CXCR4 (p=.0003), but not CCR5 (p=.71). The suppressive effects of SSRI on receptor expression did not differ as a function of depression diagnosis or depressive symptom severity. Conclusions SSRI treatment at a physiologic dose decreased CD4, CCR5 and CXCR4 expression on PBMC and macrophages ex vivo. These findings suggest that SSRI treatment, independent of depression status, downregulates HIV receptor and coreceptor expression and thus may reduce susceptibility of immune cells to HIV infection and decrease inflammation. If clinical trials confirm the present findings, ultimately there may be a role for using SSRI treatment adjunctively in HIV/AIDS.

Pharmacologic rationale for the NK1R antagonist, aprepitant as adjunctive therapy in HIV

“…The effect of aprepitant on HIV infection was assessed ex vivo using monocyte-derived macrophages (MDM) from subjects recruited in conjunction with the clinical study “Depression Antidepressants and HIV infectivity” supported by R01-MH082670 [ 25 ]. A total of 150 depressed and non-depressed HIV negative participants completed structured diagnostic psychiatric assessments (SCID) for the presence of depression, Hamilton depression rating (17-item scale) and medical evaluation.…”

Effectiveness of depression interventions for people living with HIV in Sub-Saharan Africa: A systematic review & meta-analysis of psychological & immunological outcomes

“…Selective serotonin reuptake inhibitors (SSRI) are firstline due to their efficacy and minimal adverse effects [33]. SSRI treatment may have a direct immunomodulatory effect [34] [35,36], since serotonin (5-hydroxytryptamine receptors and the 5-HT transporter are found on monocytes, macrophages, T cells, and possibly NK cells [37]. By downregulation of HIV receptor and co-receptor expression on these immune cells, treatment with SSRI may reduce susceptibility to cellular infection [34] [38].…”

Can C-reactive protein inform antidepressant medication selection in depressed outpatients? Findings from the CO-MED trial

“…Serotonergic drugs promote immune response mediated by Th1 cells whereas noradrenergic antidepressant promote immune response mediated by Th2 cells (Martino et al, 2012). SSRI medications 1) suppress the expression of cluster of differentiation 4 (CD4) glycoprotein on macrophages (Greeson et al); 2) decrease the production of interleukin (IL) 4, a key cytokine that promotes differentiation of naïve Th cells to Th2 cells (Kubera et al, 2000; Shenoy et al, 2013); 3) suppress the secretion of IL-6 which is produced by Th2 cells (Hannestad et al, 2011); and 4) increase the level of pro-inflammatory cytokines that promote Th1 cell-mediated immune response (IL-1 beta, interferon gamma [IFNγ], and tumor necrosis factor alpha [TNFα]) in the frontal cortex of rodents (Warner-Schmidt et al, 2011). Notably, Warner-Schmidt et al found that co-administration of non-steroidal inflammatory drugs (NSAIDs) not only blocked the increase in levels of inflammatory cytokines with SSRIs but also antagonized their behavioral effects in animal models of forced swim and tail suspension tests.…”