Macrophage-Derived Factors with the Potential to Contribute to Pathogenicity of HIV-1 and HIV-2: Role of CCL-2/MCP-1
Chunling Gao,
Weiming Ouyang,
Joseph Kutza,
Tobias A. Grimm,
Karen Fields,
Carla S. R. Lankford,
Franziska Schwartzkopff,
Mark Paciga,
Tzanko Stantchev,
Linda Tiffany,
Klaus Strebel,
Kathleen A. Clouse
Affiliations
Chunling Gao
Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Center for Drug Evaluation and Research, U. S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA
Weiming Ouyang
Division of Biotechnology Review and Research 2, Office of Biotechnology Products, Center for Drug Evaluation and Research, U. S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA
Joseph Kutza
Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Center for Drug Evaluation and Research, U. S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA
Tobias A. Grimm
Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Center for Drug Evaluation and Research, U. S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA
Karen Fields
Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Center for Drug Evaluation and Research, U. S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA
Carla S. R. Lankford
Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Center for Drug Evaluation and Research, U. S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA
Franziska Schwartzkopff
Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Center for Drug Evaluation and Research, U. S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA
Mark Paciga
Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Center for Drug Evaluation and Research, U. S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA
Tzanko Stantchev
Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Center for Drug Evaluation and Research, U. S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA
Linda Tiffany
Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Center for Drug Evaluation and Research, U. S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA
Klaus Strebel
Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA
Kathleen A. Clouse
Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Center for Drug Evaluation and Research, U. S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA
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.
