Substance P antagonist (CP-96,345) inhibits HIV-1 replication in human mononuclear phagocytes

Selective Serotonin Reuptake Inhibitor and Substance P Antagonist Enhancement of Natural Killer Cell Innate Immunity in Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome

“…Cerebrospinal fluid SP is elevated in depression, suggesting a pathophysiological role in depression (43), and plasma SP is elevated in HIV/AIDS, suggesting an immunophysiological role for SP in HIV/ AIDS (46). Substance P released from infected immune cells may upregulate HIV by directly facilitating HIV replication within macrophages and T cells and/or by indirectly affecting HIV proliferation through alteration of expression of β-chemokines and their receptors, which may reciprocally enhance HIV replication in these cells (79). The SP antagonist CP-96345 inhibits HIV infection of macrophages (79).…”

“…Substance P released from infected immune cells may upregulate HIV by directly facilitating HIV replication within macrophages and T cells and/or by indirectly affecting HIV proliferation through alteration of expression of β-chemokines and their receptors, which may reciprocally enhance HIV replication in these cells (79). The SP antagonist CP-96345 inhibits HIV infection of macrophages (79). These data suggest that the interaction between SP and HIV in these immune cells may have an important role in the immunopathogenesis of HIV infection and AIDS (80), and SP antagonism may upregulate NK cell immunity and enhance HIV inhibition.…”

Full-length and truncated neurokinin-1 receptor expression and function during monocyte/macrophage differentiation

“…In a mouse model, gene-targeted disruption of NK-1R protected the lung from immune complex injury, demonstrating that SP amplifies the inflammatory reaction through binding to NK-1R (28). Blocking NK-1R down-regulates CCR5 receptor expression in human monocyte-derived macrophages (29), suggesting that there is close interaction between NK-1R and ␤-chemokine receptors.…”

Neurokinin-1 Receptor (NK1-R) Expression in the Brains of SIV-Infected Rhesus Macaques

“…Our studies in human cells have demonstrated that SP enhances HIV infection of monocyte-tropic strains of HIV. 15,22 Further, NK1-R antagonists, such as CP96345 and aprepitant, inhibited M-tropic HIV by down-regulating the chemokine receptor CCR5 15,22,29 In our investigation, we examined the expression of SP and its cognate receptor NK1-R in normal and SIV-infected rhesus macaques with and without SIV encephalitis (SIVE). We demonstrate that SP in normal and SIVinfected macaques without SIV is expressed in neurons and astrocytes, primarily in the gray matter as previously reported.…”

“…9 Activation of NK1-R by SP results in increased phagocytic response in macrophages, enhanced inflammatory cytokine production by immune cells, and possible induction of a chemotactic response in monocyte macrophages, thus facilitating immune cell trafficking at sites of inflammation or infection. 16 -20 SP has a role in AIDS, and results from recent in vivo studies 1,8,15,21,22 revealed that NK1-R antagonists have an antiviral effect, 23 likely through down-regulation of CCR5 9 as well as immunomodulatory and antidepressive effects. 23,24 The major focus of existing work on SP (and its receptor-NK1-R) in macaques, however, has focused on its role as a neurotransmitter or neuromodulator and therefore the distribution of SP and NK1-R on neurons is well known, while little data exists on the in vivo distribution of SP and NK1-R on other cell types.…”