Journal of inflammation research · 2026
LncRNA TLR8-AS1 Restricts HIV-1 Infection and Inflammation in Macrophages by Suppressing Arachidonic Acid Metabolism Through NFAT1.
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Wang Fengyi, Luo Shengrui, Zhang Junhan, Zhang Yukai, Wei Hailun, Liu Jie, Mo Chuye, Jiang Junjun, Ye Li, Yuan Zongxiang
Аннотация
BACKGROUND: Long non-coding RNA (lncRNA) TLR8-AS1 has been implicated in immune regulation, but its role in HIV-1 infection remains unexplored.
METHODS: TLR8-AS1 expression was assessed in PBMCs and primary monocyte-derived macrophages (MDMs) from HIV-1/AIDS patients and healthy controls. Its subcellular localization was determined via bioinformatics, FISH, and nucleocytoplasmic fractionation. In THP-1-derived macrophages, the functional impact of TLR8-AS1 was evaluated using TLR8-AS1 overexpression and NFAT1-knockdown models; viral replication, inflammatory cytokines, and arachidonic acid (AA) metabolism were analyzed by qPCR, ELISA, and Western blot.
RESULTS: TLR8-AS1 expression levels were positively correlated with CD4+ T cell counts (r=0.439, P < 0.05), suggesting a potential association with immune status. In THP-1-derived macrophages, TLR8-AS1 overexpression significantly inhibited HIV-1 p24 production, viral gene (Pol, Vif, Nef, LTR, and Gag) expression, and secretion of IL-1β, TNF-α, and AA. Mechanistically, cytoplasmic TLR8-AS1 downregulated NFAT1 and PTGS2 (COX-2) expression, selectively suppressing the prostaglandin pathway while leaving the lipoxygenase branch (ALOX5, ALOX15) unaffected. NFAT1 knockdown reproduced the antiviral and anti-inflammatory effects of TLR8-AS1, confirming NFAT1 as a key downstream mediator. In contrast, TLR8-AS1 did not alter TLR8 or its downstream signaling molecules (MyD88 and IRF7), suggesting a TLR8-independent mechanism.
CONCLUSION: TLR8-AS1 restricts HIV-1-induced inflammation and viral replication through the NFAT1-AA axis. These findings identify TLR8-AS1 as a potential therapeutic target for mitigating chronic inflammation and viral persistence in HIV-1 infection.
METHODS: TLR8-AS1 expression was assessed in PBMCs and primary monocyte-derived macrophages (MDMs) from HIV-1/AIDS patients and healthy controls. Its subcellular localization was determined via bioinformatics, FISH, and nucleocytoplasmic fractionation. In THP-1-derived macrophages, the functional impact of TLR8-AS1 was evaluated using TLR8-AS1 overexpression and NFAT1-knockdown models; viral replication, inflammatory cytokines, and arachidonic acid (AA) metabolism were analyzed by qPCR, ELISA, and Western blot.
RESULTS: TLR8-AS1 expression levels were positively correlated with CD4+ T cell counts (r=0.439, P < 0.05), suggesting a potential association with immune status. In THP-1-derived macrophages, TLR8-AS1 overexpression significantly inhibited HIV-1 p24 production, viral gene (Pol, Vif, Nef, LTR, and Gag) expression, and secretion of IL-1β, TNF-α, and AA. Mechanistically, cytoplasmic TLR8-AS1 downregulated NFAT1 and PTGS2 (COX-2) expression, selectively suppressing the prostaglandin pathway while leaving the lipoxygenase branch (ALOX5, ALOX15) unaffected. NFAT1 knockdown reproduced the antiviral and anti-inflammatory effects of TLR8-AS1, confirming NFAT1 as a key downstream mediator. In contrast, TLR8-AS1 did not alter TLR8 or its downstream signaling molecules (MyD88 and IRF7), suggesting a TLR8-independent mechanism.
CONCLUSION: TLR8-AS1 restricts HIV-1-induced inflammation and viral replication through the NFAT1-AA axis. These findings identify TLR8-AS1 as a potential therapeutic target for mitigating chronic inflammation and viral persistence in HIV-1 infection.