HIV regulation of the IL-7R: a viral mechanism for enhancing HIV-1 replication in human macrophages in vitro.
We report a novel mechanism, involving up-regulation of the interleukin (IL)-7 cytokine receptor, by which human immunodeficiency virus (HIV) enhances its own production in monocyte-derived macrophages (MDM) in vitro. HIV-1 infection or treatment of MDM cultures with exogenous HIV-1 Tat(86) protein up-regulates the IL-7 receptor (IL-7R) alpha-chain at the levels of steady-state RNA, protein, and functional IL-7R on the cell surface (as measured by ligand-induced receptor signaling). This IL-7R up-regulation is associated with increased amounts of HIV-1 virions in the supernatants of infected MDM cultures treated with exogenous IL-7 cytokine. The overall effect of IL-7 stimulation on HIV replication in MDM culture supernatants is typically in the range of one log and greater. The results are consistent with a model in which HIV infection produces the Tat protein, which in turn up-regulates IL-7R in a paracrine manner. This results in increased IL-7R signaling in response to the IL-7 cytokine, which ultimately promotes early events in HIV replication, including binding/entry and possibly other steps prior to reverse transcription. The results suggest that the effects of IL-7 on HIV replication in MDM should be considered when analyzing and designing clinical trials involving treatment of patients with IL-7 or Tat vaccines.
Zhang
Mingjie
M
Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research & Review, Center for Biologics Evaluation & Research, FDA, 1401 Rockville Pike, Rockville, MD 20852-1448, USA.
Drenkow
Jorg
J
Lankford
Carla S R
CS
Frucht
David M
DM
Rabin
Ronald L
RL
Gingeras
Thomas R
TR
Venkateshan
Chettemegre
C
Schwartzkopff
Franziska
F
Clouse
Kathleen A
KA
Dayton
Andrew I
AI
D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D015696:Gene Products, tat / Q000502:physiology*; D015756:Genes, tat; D054303:HIV Reverse Transcriptase / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D015851:Interleukin-7 / Q000009:adverse effects / Q000494:pharmacology / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D008954:Models, Biological; D019899:Paracrine Communication; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014771:Virion; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D015851:Interleukin-7; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D054322:tat Gene Products, Human Immunodeficiency Virus; D054303:HIV Reverse Transcriptase