title: Exosomes derived from HIV-1-infected cells contain trans-activation response element RNA.
abstract: Exosomes are nano-sized vesicles produced by healthy and virus-infected cells. Exosomes derived from infected cells have been shown to contain viral microRNAs (miRNAs). HIV-1 encodes its own miRNAs that regulate viral and host gene expression. The most abundant HIV-1-derived miRNA, first reported by us and later by others using deep sequencing, is the trans-activation response element (TAR) miRNA. In this study, we demonstrate the presence of TAR RNA in exosomes from cell culture supernatants of HIV-1-infected cells and patient sera. TAR miRNA was not in Ago2 complexes outside the exosomes but enclosed within the exosomes. We detected the host miRNA machinery proteins Dicer and Drosha in exosomes from infected cells. We report that transport of TAR RNA from the nucleus into exosomes is a CRM1 (chromosome region maintenance 1)-dependent active process. Prior exposure of naive cells to exosomes from infected cells increased susceptibility of the recipient cells to HIV-1 infection. Exosomal TAR RNA down-regulated apoptosis by lowering Bim and Cdk9 proteins in recipient cells. We found 10(4)-10(6) copies/ml TAR RNA in exosomes derived from infected culture supernatants and 10(3) copies/ml TAR RNA in the serum exosomes of highly active antiretroviral therapy-treated patients or long term nonprogressors. Taken together, our experiments demonstrated that HIV-1-infected cells produced exosomes that are uniquely characterized by their proteomic and RNA profiles that may contribute to disease pathology in AIDS.
authors: National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia 20110, USA.
authors: Aarthi
authors: A
authors: Narayanan
authors: Sergey
authors: S
authors: Iordanskiy
authors: Ravi
authors: R
authors: Das
authors: Rachel
authors: R
authors: Van Duyne
authors: Steven
authors: S
authors: Santos
authors: Elizabeth
authors: E
authors: Jaworski
authors: Irene
authors: I
authors: Guendel
authors: Gavin
authors: G
authors: Sampey
authors: Elizabeth
authors: E
authors: Dalby
authors: Maria
authors: M
authors: Iglesias-Ussel
authors: Anastas
authors: A
authors: Popratiloff
authors: Ramin
authors: R
authors: Hakami
authors: Kylene
authors: K
authors: Kehn-Hall
authors: Mary
authors: M
authors: Young
authors: Caroline
authors: C
authors: Subra
authors: Caroline
authors: C
authors: Gilbert
authors: Charles
authors: C
authors: Bailey
authors: Fabio
authors: F
authors: Romerio
authors: Fatah
authors: F
authors: Kashanchi
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D042863:Cyclin-Dependent Kinase 9 / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation; D055354:Exosomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D012367:RNA, Viral; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9
keywords: AIDS; Apoptosis; Cell Cycle; Exosomes; Gag; HIV-1; Infectivity; Nef; TAR
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