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Journal of Virology, May 2009, p. 4354-4364, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.02629-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Noncytotoxic Suppression of Human Immunodeficiency Virus Type 1 Transcription by Exosomes Secreted from CD8+ T Cells{triangledown}

Ashwin Tumne,1 Varsha Shridhar Prasad,1 Yue Chen,1 Donna B. Stolz,2 Kunal Saha,3 Deena M. Ratner,1 Ming Ding,1 Simon C. Watkins,2 and Phalguni Gupta1*

Pittsburgh Retrovirus Laboratory, Department of Infectious Diseases and Microbiology, Graduate School of Public Health,1 Center for Biological Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania 15261,2 Division of Biology, Columbus State Community College, Columbus, Ohio 432153

Received 19 December 2008/ Accepted 27 January 2009

CD8+ T cells display a noncytotoxic activity that suppresses transcription of human immunodeficiency virus type 1 (HIV-1) in an antigen-independent and major histocompatibility complex-unrestricted manner. To date, the precise cellular and molecular factors mediating this CD8+ T-cell effector function remain unsolved. Despite evidence indicating the dependence of the activity on cell-cell contact, the possibility of a membrane-mediated activity that represses transcription from the viral promoter remains unexplored. We therefore investigated whether this inhibition of HIV-1 transcription might be elicited by a membrane-bound determinant. Using a CD8+ T-cell line displaying potent noncytotoxic HIV-1 suppression activity, we have identified a membrane-localized HIV-1-suppressing activity that is concomitantly secreted as 30- to 100-nm endosome-derived tetraspanin-rich vesicles known as exosomes. Purified exosomes from CD8+ T-cell culture supernatant noncytotoxically suppressed CCR5-tropic (R5) and CXCR4-tropic (X4) replication of HIV-1 in vitro through a protein moiety. Similar antiviral activity was also found in exosomes isolated from two HIV-1-infected subjects. The antiviral exosomes specifically inhibited HIV-1 transcription in both acute and chronic models of infection. Our results, for the first time, indicate the existence of an antiviral membrane-bound factor consistent with the hallmarks defining noncytotoxic CD8+ T-cell suppression of HIV-1.

* Corresponding author. Mailing address: Graduate School of Public Health, 426 Parran Hall, 130 DeSoto St., University of Pittsburgh, Pittsburgh, PA 15261. Phone: (412) 624-7998. Fax: (412) 624-4953. E-mail: pgupta1{at}pitt.edu

{triangledown} Published ahead of print on 4 February 2009.

Journal of Virology, May 2009, p. 4354-4364, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.02629-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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