title: The nerve growth factor reduces APOBEC3G synthesis and enhances HIV-1 transcription and replication in human primary macrophages.
abstract: Macrophages infected with HIV-1 sustain viral replication for long periods of time, functioning as viral reservoirs. Therefore, recognition of factors that maintain macrophage survival and influence HIV-1 replication is critical to understanding the mechanisms that regulate the HIV-1-replicative cycle. Because HIV-1-infected macrophages release the nerve growth factor (NGF), and NGF neutralization reduces viral production, we further analyzed how this molecule affects HIV-1 replication. In the present study, we show that NGF stimulates HIV-1 replication in primary macrophages by signaling through its high-affinity receptor Tropomyosin-related Kinase A (TrKA), and with the involvement of reticular calcium, protein kinase C, extracellular signal-regulated kinase, p38 kinase, and nuclear factor-κB. NGF-induced enhancement of HIV-1 replication occurred during the late events of the HIV-1-replicative cycle, with a concomitant increase in viral transcription and production. In addition, NGF reduced the synthesis of the cellular HIV-1 restriction factor APOBEC3G and also overrode its interferon-γ-induced up-regulation, allowing the production of a well-fitted virus. Because NGF-TrKA signaling is a crucial event for macrophage survival, it is possible that NGF-induced HIV-1 replication plays a role in the maintenance of HIV-1 reservoirs. Our study may contribute to the understanding of the immunopathogenesis of HIV-1 infection and provide insights about approaches aimed at limiting viral replication in HIV-1 reservoirs.
authors.affiliation: Laboratory on Thymus Research, Oswaldo Cruz Institute/Fiocruz, Rio de Janeiro, RJ, Brazil. tmoreno@ioc.fiocruz.br
authors.forename: Thiago Moreno L
authors.initials: TM
authors.lastname: Souza
authors.forename: Diego Q
authors.initials: DQ
authors.lastname: Rodrigues
authors.forename: Caroline P B
authors.initials: CP
authors.lastname: Passaes
authors.forename: Victor
authors.initials: V
authors.lastname: Barreto-de-Souza
authors.forename: Renato S
authors.initials: RS
authors.lastname: Aguiar
authors.forename: Jairo R
authors.initials: JR
authors.lastname: Temerozo
authors.forename: Mariza G
authors.initials: MG
authors.lastname: Morgado
authors.forename: Carlos Frederico L
authors.initials: CF
authors.lastname: Fontes
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Araujo
authors.forename: Dumith Chequer
authors.initials: DC
authors.lastname: Bou-Habib
mesh_terms: D000071480:APOBEC-3G Deaminase; D015153:Blotting, Western; D003564:Cytidine Deaminase / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D015658:HIV Infections / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000821:virology*; D020932:Nerve Growth Factor / Q000378:metabolism*; D020917:Receptor, trkA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D014779:Virus Replication / Q000502:physiology*
chemical_list: D020932:Nerve Growth Factor; D020917:Receptor, trkA; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase