Interleukin-10 enhances tumor necrosis factor-alpha activation of HIV-1 transcription in latently infected T cells.
Interleukin-10 (IL-10) is elevated in HIV-1-infected individuals and has been implicated in disease progression. We previously reported that IL-10 cooperates with tumor necrosis factor-alpha (TNF-alpha) to activate HIV-1 expression synergistically in acutely infected monocyte-derived macrophages and the chronically infected U1 promonocytic cell line. To determine whether IL-10 also cooperates with TNF-alpha to activate latent HIV-I expression in lymphocytes, we examined the effects of IL-10 on proviral expression in the chronically infected T-cell line, ACH-2. Although IL-10 inhibited HIV-1 expression acting alone, in combination with suboptimal concentrations of TNF-alpha, IL-10 increased HIV-1 steady-state mRNA expression and p24 core antigen production in ACH-2 cells. Interestingly, IL-10 concentrations that synergistically induced virus also maximally stimulated endogenous TNF-alpha expression, suggesting that cell-derived TNF-alpha may contribute to cytokine synergy. Transfection studies in ACH-2 cells indicated that IL-10 combined with TNF-alpha to activate the HIV-1 long terminal repeat (LTR). IL-10 also cooperated with TNF-alpha to activate HIV-1 LTR in 1G5 cells, a Jurkat T-cell line stably transfected with an LTR-dependent luciferase reporter gene. Pyrrolidine dithiocarbamate, a potent transcriptional inhibitor of the viral LTR, abrogated the cytokine responses in both U1 and ACH-2 cells, suggesting a common TNF-alpha-mediated transcriptional mechanism in these cell types despite their different modes of provirus latency. Taken collectively, these data suggest that IL-10 enhances suboptimal TNF-alpha activation of HIV-1 transcription in chronically infected T-cells at least in part through induction of endogenous TNF-alpha expression.
Rabbi
M F
MF
Department of Immunology/Microbiology, Rush Presbyterian St. Luke's Medical School Chicago, Illinois, USA.
Finnegan
A
A
Al-Harthi
L
L
Song
S
S
Roebuck
K A
KA
D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D017930:Genes, Reporter; D016325:HIV Long Terminal Repeat / Q000187:drug effects / Q000502:physiology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012367:RNA, Viral / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000821:virology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology / Q000502:physiology*
D012333:RNA, Messenger; D012367:RNA, Viral; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10