Selective serotonin reuptake inhibitor and substance P antagonist enhancement of natural killer cell innate immunity in human immunodeficiency virus/acquired immunodeficiency syndrome

Abstract

Background: Natural killer (NK) cells play an important role in innate immunity and are involved in the host defense against human immunodeficiency virus (HIV) infection. This study examines the potential role of three underlying regulatory systems that have been under investigation in central nervous system research as well as immune and viral research: serotonin, neurokinin, and glucocorticoid systems.

Methods: Fifty-one HIV-seropositive subjects were recruited to achieve a representative sample of depressed and nondepressed women. The effects of a selective serotonin reuptake inhibitor (SSRI), a substance P (SP) antagonist, and a glucocorticoid antagonist on NK cell function were assessed in a series of ex vivo experiments of peripheral blood mononuclear cells from each HIV-seropositive subject.

Results: Natural killer cell cytolytic activity was significantly increased by the SSRI citalopram and by the substance P antagonist CP-96345 relative to control conditions; the glucocorticoid antagonist, RU486, showed no effect on NK cytotoxicity. Our results suggest that the effects of the three agents did not differ as a function of depression.

Conclusions: Our findings provide evidence that NK cell function in HIV infection may be enhanced by serotonin reuptake inhibition and by substance P antagonism. It remains to be determined if HIV-related impairment in not only NK cytolytic activity but also NK noncytolytic activity can be improved by an SSRI or an SP antagonist. Clinical studies are warranted to address these questions and the potential roles of serotonergic agents and SP antagonists in improving NK cell immunity, delaying HIV disease progression, and extending survival with HIV infection.

Figure 1

Ex vivo increase in log₁₀ NK cell activity (lytic units) in PBMCs from 51 HIV-seropositive women treated with SSRI, citalopram (10⁻⁶ mol/L); SP-A, CP-96345 (10⁻⁶ mol/L); GC-A, RU486 (10⁻⁶ mol/L). SSRI: p<.001; SP-A: p=.01; GC-A: p=.69. GC-A, glucorticoid antagonist; HIV, human immunodeficiency virus; NK, natural killer; PBMC, peripheral blood mononuclear cell; SP-A, substance P antagonist; SSRI, selective serotonin reuptake inhibitor.