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

Abstract

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 membranemediated 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 endosomederived 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.

Antigen-specific, antibody-coated, exosome-like nanovesicles deliver suppressor T-cell microRNA-150 to effector T cells to inhibit contact sensitivity

“…Besides CD4 + Tregs, there are many clinical instances in which a role for regulatory CD8 + T cells has been described. These include regulation of IgE-mediated allergy 69 , autoimmunity 70,71 , viral diseases 72-74 cancer 75,76 and transplantation alloimmunity 77 . CD8 + Treg are being appreciated to play a role in a variety of regulatory processes 78-80 .…”

Classification, Functions, and Clinical Relevance of Extracellular Vesicles

“…Exosomes also have anti-HIV-1 activity (Tumne et al, 2009), and the human cytidine deaminase APOBEC3G, which is a part of a cellular defense system against HIV-1 and other retroviruses, is secreted in exosomes and is actually the major exosomal component explaining the anti-HIV-1 activity of exosomes (Khatua et al, 2009(Khatua et al, , 2010. Furthermore, vesicles from virus-infected cells can present antigens to activate the immune system (Walker et al, 2009;Meckes and Raab-Traub, 2011).…”

Immune Surveillance Properties of Human NK Cell-Derived Exosomes

“…The major hypothesis on their cellular origin involves a process of endosometo-lysosome-to-phagosome fusion that often includes the plasma membrane, with the final formation of ad hoc structures called multivesicular bodies (10). Exosomes have been shown to be involved in a variety of functions related to their cellular source, including immune stimulation or suppression, cell-to-cell communication, delivery of proteins and genetic material, cell-free viral infection, tumor immune escape, and tumor cell communication (10)(11)(12)(13)(14)(15)(16)(17). One example of the bioactivity of exosomes is their capacity to trigger cell death through ligands for death receptors, such as FasL carried by these nanovesicles (2,18).…”