Evidence of the innate antiviral and neuroprotective properties of progranulin.

TitleEvidence of the innate antiviral and neuroprotective properties of progranulin.
Publication TypeJournal Article
Year of Publication2014
AuthorsSuh, H-S, Lo, Y, Choi, N, Letendre, S, Lee, SC
JournalPLoS One
Date Published2014
KeywordsAdult, CHARTER, Cognition, External, Female, HIV, HIV Infections, Humans, Inflammation, Intercellular Signaling Peptides and Proteins, Male, Microglia, Multivariate Analysis, Progranulins, Viral Load, Virus Replication

BACKGROUND: Compelling data exist that show that normal levels of progranulin (PGRN) are required for successful CNS aging. PGRN production is also modulated by inflammation and infection, but no data are available on the production and role of PGRN during CNS HIV infection.METHODS: To determine the relationships between PGRN and HIV disease, neurocognition, and inflammation, we analyzed 107 matched CSF and plasma samples from CHARTER, a well-characterized HIV cohort. Levels of PGRN were determined by ELISA and compared to levels of several inflammatory mediators (IFNγ, IL-6, IL-10, IP-10, MCP-1, TNFα, IL-1β, IL-4 and IL-13), as well as clinical, virologic and demographic parameters. The relationship between HIV infection and PGRN was also examined in HIV-infected primary human microglial cultures.RESULTS: In plasma, PGRN levels correlated with the viral load (VL, p<0.001). In the CSF of subjects with undetectable VL, lower PGRN was associated with neurocognitive impairment (p = 0.046). CSF PGRN correlated with CSF IP-10, TNFα and IL-10, and plasma PGRN correlated with plasma IP-10. In vitro, microglial HIV infection increased PGRN production and PGRN knockdown increased HIV replication, demonstrating that PGRN is an innate antiviral protein.CONCLUSIONS: We propose that PGRN plays dual roles in people living with HIV disease. With active HIV replication, PGRN is induced in infected macrophages and microglia and functions as an antiviral protein. In individuals without active viral replication, decreased PGRN production contributes to neurocognitive dysfunction, probably through a diminution of its neurotrophic functions. Our results have implications for the pathogenesis, biomarker studies and therapy for HIV diseases including HIV-associated neurocognitive dysfunction (HAND).

Alternate JournalPLoS ONE
PubMed ID24878635
PubMed Central IDPMC4039467
Grant ListHHSN271201000036C / / PHS HHS / United States
KO1 MH084705 / MH / NIMH NIH HHS / United States
P30AI051519 / AI / NIAID NIH HHS / United States
R01 MH55477 / MH / NIMH NIH HHS / United States
HHSN271201000030C / / PHS HHS / United States
P30 MH062512 / MH / NIMH NIH HHS / United States
N01 MH22005 / MH / NIMH NIH HHS / United States
1S10RR031646 / RR / NCRR NIH HHS / United States