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Substance P antagonist (CP-96,345) inhibits HIV-1 replication in human mononuclear phagocytes
1Division of Immunologic and Infectious Diseases, Joseph Stokes, Jr., Research Institute, Children's Hospital of Philadelphia, Philadelphia, PA 19104-4399, USA.
Abstract:
Substance P (SP) is a potent modulator of neuroimmunoregulation. We recently reported that human immune cells express SP and its receptor. We have now investigated the possible role that SP and its receptor plays in HIV infection of human mononuclear phagocytes. SP enhanced HIV replication in human blood-isolated mononuclear phagocytes, whereas the nonpeptide SP antagonist (CP-96,345) potently inhibited HIV infectivity of these cells in a concentration-dependent fashion. CP-96,345 prevented the formation of typical giant syncytia induced by HIV Bal strain replication in these cells. This inhibitory effect of CP-96,345 was because of the antagonism of neurokinin-1 receptor, a primary SP receptor. Both CP-96,345 and anti-SP antibody inhibited SP-enhanced HIV replication in monocyte-derived macrophages (MDM). Among HIV strains tested (both prototype and primary isolates), only the R5 strains (Bal, ADA, BL-6, and CSF-6) that use the CCR5 coreceptor for entry into MDM were significantly inhibited by CP-96,345; in contrast, the X4 strain (UG024), which uses CXCR4 as its coreceptor, was not inhibited. In addition, the M-tropic ADA (CCR5-dependent)-pseudotyped HIV infection of MDM was markedly inhibited by CP-96,345, whereas murine leukemia virus-pseudotyped HIV was not affected, indicating that the major effect of CP-96,345 is regulated by Env-determined early events in HIV infection of MDM. CP-96,345 significantly down-regulated CCR5 expression in MDM at both protein and mRNA levels. Thus, SP-neurokinin-1 receptor interaction may play an important role in the regulation of CCR5 expression in MDM, affecting the R5 HIV strain infection of MDM.
Insights
Substance P (SP) enhances HIV replication in immune cells. Blocking the SP receptor with CP-96,345 inhibits HIV infectivity, particularly R5 strains, by down-regulating CCR5 expression.
Area of Science:
- Neuroimmunology
- Virology
- Cell Biology
Background:
- Substance P (SP) modulates neuroimmunoregulation and is expressed by human immune cells.
- SP and its receptor's role in HIV infection of mononuclear phagocytes requires investigation.
Purpose of the Study:
- To investigate the role of SP and its receptor in HIV infection of human mononuclear phagocytes.
- To determine the effect of SP receptor antagonism on HIV replication and infectivity.
Main Methods:
- Assessing HIV replication and infectivity in human mononuclear phagocytes treated with SP and an SP antagonist (CP-96,345).
- Evaluating the impact of CP-96,345 on syncytia formation and HIV strain-specific infectivity (R5 vs. X4).
- Quantifying CCR5 expression levels (protein and mRNA) in response to CP-96,345 treatment.
Main Results:
- SP enhanced HIV replication; CP-96,345 inhibited HIV infectivity and syncytia formation in a dose-dependent manner.
- CP-96,345 specifically inhibited R5 HIV strains but not X4 strains, indicating an Env-determined early event.
- CP-96,345 significantly reduced CCR5 expression at both protein and mRNA levels in monocyte-derived macrophages (MDM).
Conclusions:
- SP-neurokinin-1 receptor interaction is crucial for regulating CCR5 expression in MDM.
- Antagonism of the SP receptor (neurokinin-1) inhibits R5 HIV strain infection by down-regulating CCR5.
- This pathway represents a potential therapeutic target for managing HIV infection.