Abstract: Objective: To explore the relationship between serine protease inhibitor E family member 1 (SerpinE1) and human immunodeficiency virus type 1 (HIV-1) infection, as well as the role and mechanism of SerpinE1 as a protease inhibitor in macrophages in the process of HIV infection. Methods: Groups were matched according to age and gender characteristics to recruit untreated HIV infected patients HIV ART (-) group and healthy controls (HC group), and the expression of SerpinE1 mRNA in peripheral blood mononuclear cells (PBMCs) was detected. SerpinE1 knockdown cells were constructed on THP-1 cells (knock-down SerpinE1 group), infected or uninfected with HIV BaL. The expression levels of HIV-p24 and interferon (IFN)-α protein were detected by enzyme-linked immunosorbent assay (ELISA). The differential genes and KEGG enrichment pathways between knock-down SerpinE1 group and control group after exposure were analyzed by transcriptome sequencing. The mRNA expression levels of HIV Gag, Toll-like receptor 7 (TLR7), Toll-like receptor 8 (TLR8), interleukin-1β (IL-1β), MX dynamin-like GTPase 1 (MX1) and MX2 were detected by reverse transcription-quantitative PCR (RT-qPCR). The protein expression levels of JAK2, STAT1, STAT2, SATA4, IL-1β and MX1 were detected by western blotting. Results: Compared with the HC group, SerpinE1 was lowly expressed in in the HIV ART (-) group, and could be down-regulated by HIV in THP-1-derived macrophages (P＜0.05). Knockdown of SerpinE1 expression down-regulated HIV-p24 protein expression and HIV Gag mRAN expression, promoted IFN-α protein secretion level, and enhanced the expression of TLR7, TLR8, Janus kinase 2 (JAK2), signal transducer and activator of transcription (STAT) protein family members STAT1, STAT2, STAT4, IL-1β, MX1, and MX2 (P＜0.05). Conclusion: SerpinE1 may reduce the release of IFN by inhibiting the activation of TLR7 and TLR8 signaling pathways, and then inhibit the JAK/STAT pathway and its induced expression of various IFN stimulated genes and IFN-related factors, thereby promoting HIV-1 infection and replication.