Project 3: Targeting Neurokinin 1 Receptor

Temple Univ Of The Commonwealth, Philadelphia PA

Investigators

Linked publications & trials

Abstract

Abstract This project one of 3 projects in an IPCP which is the result of a joint interaction between NIMH supported research centers at Temple University and UPenn/Children's Hospital of Philadelphia. The overall proposal is targeting HIV reservoir in CNS through three interlinked therapeutic interventions in macrophage polarization which normally promotes creation and maintenance HIV reservoir in CNS. In project 3 we propose that CNS infiltrating cells of monocytes/macrophage lineage are exposed to high levels of SP creating favorable conditions for HIV replication through increased survival of monocytes/macrophages in CNS, higher levels of HIV replication in SP polarized infected cells and recruitment of additional cells. We will correlate expression of SP, NK1R, chemokines and chemokine receptors as well as macrophage M2 polarization and survival markers with HIV infection and CNS cell infiltration. In addition we will use a panel of postmortem brain tissues from HIV infected individuals, obtained from the NNTC, with and without HAND and HIVE to validate in vitro results. We also test our hypothesis using Rhesus macaque infected with SIV, is the best available animal model for the study of AIDS pathogenesis in general and of the neuropathogenesis of AIDS in particular. We will investigate three unique mechanisms that contribute to the facilitating effect of SP on HIV replication in polarized monocytes and macrophages. In Aim 1 we will determine the role of SP in monocyte migration and trafficking into CNS. SP affects monocytes maturation and polarization of macrophages, defined by surface markers and cytokine production, leading to a distinctive and unique macrophage phenotype different from classical or alternative polarization. In Aim 2 we characterize this phenotype and its effect on HIV replication. SP promotes survival in various cell types, including lymphocytes. SP treatment also has anti-apoptotic outcome. The effect of SP on monocyte cell survival may be an additional mechanism that explains the facilitating effect of SP on HIV replication. Therefore, in Aim 3 we will focus on examining anti-apoptotic role of SP in HIV infection. Since SP is found in high concentrations in the cellular microenvironment in the brain, we hypothesize that brain macrophages in HIV-infected individuals have phenotypes consistent with exposure to high concentrations of SP. In Aim 4 we will test our hypothesis using Rhesus macaque in vivo model and treatment with SP antagonist aprepitant in addition to cART and other novel compounds identified in projects 1 and 2 to evaluate role of immune polarization of macrophages in SIV infection of CNS. We propose combination of cART therapy with NK1R, M-CSF/cFMS and adenosine/Adora 2B antagonists that block M2 polarization of macrophages. This proposal is focuses on the mechanisms of HIV/AIDS neuropathogenesis and has direct implications for development of novel neuroAIDS therapy and eradication of viral reservoirs.