SOCS1 is an inducible host factor during HIV-1 infection and regulates the intracellular trafficking and stability of HIV-1 Gag

doi:10.1073/pnas.0704831105

SOCS1 is an inducible host factor during HIV-1 infection and regulates the intracellular trafficking and stability of HIV-1 Gag

^aDepartment of Pathology, Yokohama City University School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan;
^bAIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan;
^dKitasato Institute for Life Sciences, Kitasato University, Shirokane 5-9-1, Minato-ku, Tokyo 108-8641, Japan;
^eDepartment of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan;
^fMolecular Oncology Laboratory, Department of Pathology, Royal College of Surgeons in Ireland, Smurfit Building, Beaumont Hospital, Dublin 9, Ireland;
^hDepartment of Biochemistry II, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan;
^gDepartment of Biological Science and Technology, Science University of Tokyo, 2641 Yamazaki, Noda, Chiba 278-8510, Japan;
ⁱDivision of Hematology and Oncology, Shizuoka Children's Hospital, 860 Urushiyama, Aoi-ku, Shizuoka 420-8660, Japan;
^jDivision of Clinical Retrovirology and Infectious Diseases, Center for AIDS Research, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan;
^kDivision of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan; and
^lCell Free Science and Research Center, Ehime University, Ehime 790-8577, Japan

Edited by Robert C. Gallo, University of Maryland, Baltimore, MD, and approved November 19, 2007 (received for review May 24, 2007)

Abstract

Human immunodeficiency virus type 1 (HIV-1) utilizes the macromolecular machinery of the infected host cell to produce progeny virus. The discovery of cellular factors that participate in HIV-1 replication pathways has provided further insight into the molecular basis of virus–host cell interactions. Here, we report that the suppressor of cytokine signaling 1 (SOCS1) is an inducible host factor during HIV-1 infection and regulates the late stages of the HIV-1 replication pathway. SOCS1 can directly bind to the matrix and nucleocapsid regions of the HIV-1 p55 Gag polyprotein and enhance its stability and trafficking, resulting in the efficient production of HIV-1 particles via an IFN signaling-independent mechanism. The depletion of SOCS1 by siRNA reduces both the targeted trafficking and assembly of HIV-1 Gag, resulting in its accumulation as perinuclear solid aggregates that are eventually subjected to lysosomal degradation. These results together indicate that SOCS1 is a crucial host factor that regulates the intracellular dynamism of HIV-1 Gag and could therefore be a potential new therapeutic target for AIDS and its related disorders.

Footnotes

^cTo whom correspondence may be addressed. E-mail: aryo{at}nih.go.jp or nyama{at}nih.go.jp
Author contributions: A.R. and N.T. contributed equally to this work; A.R., A.Y., Y.M., and N.Y. designed research; A.R., N.T., K.O., R.K., M.N., H.S., S.H., T.S., I.A., and Y.M. performed research; J.K., S.H., M.Y., J.C., J.-i.M., K.Y., S.M., M.H., and A.Y. contributed new reagents/analytic tools; A.R., N.T., K.O., M.N., H.S., K.P., M.Y., K.Y., S.M., T.S., I.A., Y.M., and N.Y. analyzed data; and A.R., K.P., and N.Y. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0704831105/DC1.
Freely available online through the PNAS open access option.