Background: HIV-1 persistently replicates in CD4⁺ T cells and macrophages in different tissues, where the presence of cytokines and other soluble mediators can modulate HIV-1 production. It has been described that HIV-1 infection induces the release of nerve growth factor (NGF), which is essential to macrophage survival and virus replication. Thus, we evaluated whether NGF, and other neurotrophins, could modulate HIV-1 replication in human primary cells and characterized the mechanisms underlining this phenomenon.

Methods: HIV-1-infected peripheral blood mononuclear cells (PBMC) and macrophages were treated with NGF, BDNF, and proNGF. Viral replication was measured by anti-p24 enzyme-linked immunosorbent assay (ELISA) in culture supernatants. To analyze the possible signaling pathway involved in NGF-induced HIV-1 replication different pharmacological inhibitors were employed. Participation of APOBEC3G was evaluated in macrophages exposed to NGF, by means of real-time polymerase chain reaction (RT-PCR) and immunoblotting. Statistical analyzes were performed using Student's t test and the software Graphpad Prism

Results: We found that NGF, BDNF, and proNGF stimulated HIV-1 replication in macrophages, reaching as much as a 20-fold increase for NGF at 10 ng/mL (n = 12, p <0.008). NGF effects were cell-type dependent, since it had no effect in HIV-1-infected PBMC (n = 4, p >0.05). Results of cell-signaling pathways suggest that the NGF-induced HIV-1 production involves engagement of TrKA receptor, mobilization of intracellular calcium, triggering PKC signaling, leading to activation of ERK, p38kinase, and NfkB (n = 4, p <0,009). The NGF effect on HIV-1 replication may not depend on TNF and MIF release(n = 3, p >0,05). We also observed a decrease of APOBEC3G production in NGF-treated macrophages (n = 4).

Conclusions: Since NGF-TrKA signaling is a crucial event for macrophage survival, we believe that the NGF-induced HIV-1 replication contribute for the maintenance of HIV-1 reservoirs. Besides, our study could help to elucidate a new feature of the interface between HIV-1/cellular physiology and can, therefore, provide new basis for the development of novel antiretroviral therapies.