Noncytotoxic suppression of human immunodeficiency virus type 1 transcription by exosomes secreted from CD8+ T cells.
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.
Tumne
Ashwin
A
Department of Infectious Diseases and Microbiology, Pittsburgh Retrovirus Laboratory, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. pgupta1@pitt.edu
Prasad
Varsha Shridhar
VS
Chen
Yue
Y
Stolz
Donna B
DB
Saha
Kunal
K
Ratner
Deena M
DM
Ding
Ming
M
Watkins
Simon C
SC
Gupta
Phalguni
P
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000648:ultrastructure; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology; D055354:Exosomes / Q000276:immunology* / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D046529:Microscopy, Electron, Transmission; D011401:Promoter Regions, Genetic / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*; D014779:Virus Replication
D050794:STAT1 Transcription Factor