Interleukin-7 induces HIV replication in primary naive T cells through a nuclear factor of activated T cell (NFAT)-dependent pathway.
Interleukin (IL)-7 plays several roles critical to T cell maturation, survival, and homeostasis. Because of these functions, IL-7 is under investigation as an immune-modulator for therapeutic use in lymphopenic clinical conditions, including HIV. We reported that naive T cells, typically not permissive to HIV, can be productively infected when pre-treated with IL-7. We evaluated the mechanism by which IL-7-mediates this effect. IL-7 potently up-regulated the transcriptional factor NFAT, but had no effect on NFkappaB. Blocking NFAT activity using a number of reagents, such as Cyclosporin A, FK-506, or the NFAT-specific inhibitor known as VIVIT peptide, all markedly reduced IL-7-mediated induction of HIV replication in naive T cells. Additional neutralization of cytokines present in IL-7-treated cultures and/or those that have NFAT-binding sequences within their promotors indicated that IL-10, IL-4, and most significantly IFNgamma, all contribute to IL-7-induction of HIV productive replication in naive T cells. These data clarify the mechanism by which IL-7 can overcome the block to HIV productive infection in naive T cells, despite their quiescent cell status. These findings are relevant to the treatment of HIV disease and understanding HIV pathogenesis in the naive CD4+ T cell compartment, especially in light of the vigorous pursuit of IL-7 as an in vivo immune modulator.
Managlia
Elizabeth Z
EZ
Department of Immunology/Microbiology, Rush University Medical Center, 1735 West Harrison Street, 614 Cohn, Chicago, IL 60612, USA.
Landay
Alan
A
Al-Harthi
Lena
L
D015703:Antigens, CD / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D006678:HIV / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D015851:Interleukin-7 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D050778:NFATC Transcription Factors / Q000378:metabolism*; D012016:Reference Values; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology*; D014779:Virus Replication / Q000187:drug effects* / Q000276:immunology
D015703:Antigens, CD; D015851:Interleukin-7; D050778:NFATC Transcription Factors