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19 R-113281 (a Combined Tachykinin Receptor Antagonist) Potently Inhibits HIV-1 Infection of Human Blood Mononuclear Phagocytes
J.-P. Lai*, X. Wang, T. Nishi, Y. Li, L. Song, W.-Z. Ho, and S. D. Douglas
The Children's Hosp. of Philadelphia, Univ. of Pennsylvania Sch. of Med., Philadelphia, USA
Background: Substance P (SP) is a potent modulator of neuroimmunoregulation. SP affects macrophage function in an autocrine manner. SP-neurokinin 1 receptor (SP Receptor) interaction is an important trigger of intracellular events and may be involved in modulation of HIV infection of human blood monocyte-derived macrophage (MDM). We investigated the hypothesis that interruption of SP autocrine loop by SP antagonist affects HIV infection of human MDM.
Methods: MDM were treated with or without the SP antagonist R113281 or its inactive enantiomer, r-113281, for 2 h. The MDM were then infected with HIV overnight. Untreated and HIV-infected MDM were used as controls. Culture supernatants were harvested for HIV RT activity, and cellular RNA was extracted for HIV gag mRNA expression using real-time RT-PCR.
Results: SP enhanced HIV replication in MDM, whereas R-113281 inhibited HIV infectivity of MDM in a concentration-dependent manner by 80% (10(6 m), 69% (10(7 m), and 46% (10(8 m), respectively. r113281 failed to inhibit HIV Bal replication. Among HIV strains tested only R5 strains, both prototype and primary isolates (Bal, BL-4, and CSF-6), were significantly inhibited by R113281, whereas X4 strain (UG024) was not affected. Furthermore, ADA-pseudotype HIV infection of MDM was markedly inhibited by R113281, whereas MLV-pseudotyped HIV was not affected, indicating that the effect of R113281 is regulated by env-determined early events. In addition, CCR5 expression on MDM was down-regulated by R113281. SP significantly increased HIV LTR-driven luciferase activity, which was abrogated by R113281, indicating that SP activates HIV LTR through the SP receptors on the cell membrane.
Conclusions: R113281 inhibits HIV replication in human MDM by interrupting the SP autocrine loop, resulting in down-regulation of CCR5 expression and antagonism of the SP effect on activation of HIV LTR promoter.
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