Abstract
The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) are key molecules in the central nervous system development, which also exert specific effects on cells of the immune system. With regard to the latter, in vitro as well as in vivo data suggested that neurotrophins may play a role in human immunodeficiency virus (HIV) infection, especially in perivascular spaces where infiltrated macrophages express NGF. In the present study, we examined the expression of neurotrophins and their receptors in human monocyte-derived macrophages (MDMs) during infection by the R5 prototype HIV1/Ba-L strain. We then assessed to what extent neurotrophins themselves modulate infected macrophage survival and the level of virus production. The data show that neurotrophins and neurotrophin receptors are not modulated during HIV replication. Likewise, exogenous neurotrophins, or alternatively the blocking of neurotrophin receptors, neither modulated MDM sensitivity to HIV infection and replication nor altered their viability. In contrast, NGF clearly increased CD184 expression in macrophages, but this did not sensitize them to the X4 isolate HIV-1/Lai infection. Nevertheless, NGF enhanced monocyte chemotactic response to low CXCL-12 concentration regardless of infection. Surprisingly, CXCL-12–attracted monocytes from NGF-stimulated, HIV-infected cultures produced decreased amounts of virus progeny than their non–NGF-stimulated counterparts. This suggests a preferential effect on uninfected monocytes. Together these findings suggest a role for NGF in the continuous attraction of activated monocytes to the perivascular spaces, contributing to the chronic inflammatory state rather than neuroinvasion by HIV.
Acknowledgements
This work was supported by grants from the “Agence Nationale de Recherche sur le SIDA” (ANRS) and “Ensemble Contre le SIDA” (Sidaction), and recurrent funds of the “Commissariat à l'Energie Atomique” (CEA). Boubekeur Samah and Fabrice Porcheray hold doctoral fellowships from the ANRS. Fabrice Porcheray was a recipient of a fellowship from the “Fondation pour la Recherche Médicale” (FRM). Boubekeur Samah is a recipient of a fellowship from “Ensemble Contre le SIDA” (Sidaction). The authors warmly thank Julie DeVito for kindly and accurately correcting the manuscript.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.