Macrophage-Derived Factors with the Potential to Contribute to Pathogenicity of HIV-1 and HIV-2: Role of CCL-2/MCP-1

• Published in: Viruses Vol. 15; no. 11; p. 2160
• Main Authors: Gao, Chunling, Ouyang, Weiming, Kutza, Joseph, Grimm, Tobias A, Fields, Karen, Lankford, Carla S R, Schwartzkopff, Franziska, Paciga, Mark, Stantchev, Tzanko, Tiffany, Linda, Strebel, Klaus, Clouse, Kathleen A
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 27.10.2023
• Subjects: Acquired immune deficiency syndrome; AIDS; Blood & organ donations; CCL2; Cells, Cultured; Chemokine CCL2 - metabolism; Chemokines; CULLIN 2; Development and progression; Disease; DNA microarrays; Gene expression; Gene Expression Regulation; HIV; HIV infection; HIV Infections - metabolism; HIV Infections - virology; HIV Seropositivity; HIV-1; HIV-1 - genetics; HIV-2; HIV-2 - genetics; Human immunodeficiency virus; Humans; Immune response; Immune system; Infections; Interferon; macrophage; Macrophages; Medical research; Medicine, Experimental; Monocyte chemoattractant protein 1; Monocytes; Pathogenesis; Pathogenicity; Physiological aspects; Proteasomes; Proteins; Reagents; STAT1; Stat1 protein; Ubiquitin-protein ligase; Viral infections; Virulence; Virus Replication; Western blotting; United States; United States > US; HIV-1; HIV-2; STAT1; CCL2; macrophage; CULLIN 2; RBX1
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v15112160

Human immunodeficiency virus type 2 (HIV-2) is known to be less pathogenic than HIV-1. However, the mechanism(s) underlying the decreased HIV-2 pathogenicity is not fully understood. Herein, we report that β-chemokine CCL2 expression was increased in HIV-1-infected human monocyte-derived macrophages (MDM) but decreased in HIV-2-infected MDM when compared to uninfected MDM. Inhibition of CCL2 expression following HIV-2 infection occurred at both protein and mRNA levels. By microarray analysis, quantitative PCR, and Western blotting, we identified that Signal Transducer and Activator of Transcription 1 (STAT1), a critical transcription factor for inducing CCL2 gene expression, was also reduced in HIV-2-infected MDM. Blockade of STAT1 in HIV-infected MDM using a STAT1 inhibitor significantly reduced the production of CCL2. In contrast, transduction of STAT1-expressing pseudo-retrovirus restored CCL2 production in HIV-2-infected MDM. These findings support the concept that CCL2 inhibition in HIV-2-infected MDM is meditated by reduction of STAT1. Furthermore, we showed that STAT1 reduction in HIV-2-infected MDM was regulated by the CUL2/RBX1 ubiquitin E3 ligase complex-dependent proteasome pathway. Knockdown of CUL2 or RBX1 restored the expression of STAT1 and CCL2 in HIV-2-infected MDM. Taken together, our findings suggest that differential regulation of the STAT1-CCL2 axis may be one of the mechanisms underlying the different pathogenicity observed for HIV-1 and HIV-2.