Prothymosin-alpha inhibits HIV-1 via Toll-like receptor 4-mediated type I interferon induction.
Induction of type I interferons (IFN) is a central feature of innate immune responses to microbial pathogens and is mediated via Toll-like receptor (TLR)-dependent and -independent pathways. Prothymosin-alpha (ProTalpha), a small acidic protein produced and released by CD8(+) T cells, inhibits HIV-1, although the mechanism for its antiviral activity was not known. We demonstrate that exogenous ProTalpha acts as a ligand for TLR4 and stimulates type I IFN production to potently suppress HIV-1 after entry into cells. These activities are induced by native and recombinant ProTalpha, retained by an acidic peptide derived from ProTalpha, and lost in the absence of TLR4. Furthermore, we demonstrate that ProTalpha accounts for some of the soluble postintegration HIV-1 inhibitory activity long ascribed to CD8(+) cells. Thus, a protein produced by CD8(+) T cells of the adaptive immune system can exert potent viral suppressive activity through an innate immune response. Understanding the mechanism of IFN induction by ProTalpha may provide therapeutic leads for IFN-sensitive viruses.
Mosoian
Arevik
A
Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA. arevik.mosoian@mssm.edu
Teixeira
Avelino
A
Burns
Colin S
CS
Sander
Leif E
LE
Gusella
G Luca
GL
He
Cijiang
C
Blander
J Magarian
JM
Klotman
Paul
P
Klotman
Mary E
ME
D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000276:immunology / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000276:immunology / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D066298:In Vitro Techniques; D007370:Interferon Type I / Q000096:biosynthesis* / Q000235:genetics; D008024:Ligands; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D011498:Protein Precursors / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D013947:Thymosin / Q000031:analogs & derivatives* / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000187:drug effects* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
D033942:Adaptor Proteins, Vesicular Transport; D019380:Anti-HIV Agents; D007370:Interferon Type I; D008024:Ligands; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D011498:Protein Precursors; D012333:RNA, Messenger; D011994:Recombinant Proteins; C470409:TICAM1 protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C040782:prothymosin alpha; D013947:Thymosin