title: Induction of HIV-1 replication by type 1-like cytokines, interleukin (IL)-12 and IL-15: effect on viral transcriptional activation, cellular proliferation, and endogenous cytokine production.
abstract: Cytokine dysregulation is evident in HIV-1 infection and it may play an important role in HIV-1 pathogenesis. Administration of T helper cytokines potentially may restore the functional abnormalities to the HIV-1 immune response. Type 1-like cytokines, IL-2, IL-12, and IL-15, are candidates for immune-based therapy for HIV. Given their potential therapeutic use, we determined the effects of IL-2, IL-12, and IL-15 on HIV-1 replication in both primary blood mononuclear cells (PBMC) and the T-cell line, Kit 225-K6. We demonstrate that both IL-2 and IL-12 induce a similar level of HIV-1 replication (9- and 11-fold, respectively) in mitogen-stimulated PBMC. The effect of IL-2 plateaued by day 6, while that of IL-12 continued to increase HIV-1 expression. IL-15 induced a 2.5-fold increase in HIV-1 expression that remained at the same level through day 6. In Kit 225-K6, an IL-2-dependent T cell line, IL-12 and IL-15 enhanced HIV-1 replication by 5- and 3.5-fold over IL-2-treated cultures, respectively. IL-2-, IL-12-, and IL-15-mediated induction of HIV was independent of direct HIV-1 LTR activation, since none of the cytokines induced LTR activity from transfected reporter gene constructs. The cytokine-mediated induction of HIV-1 expression was also independent of cellular proliferation. In PBMC, the IL-12-mediated effect was partially mediated by endogenous cytokine production of IL-1beta and IL-7, whereas in Kit 225-K6, TNFalpha, INFgamma, IL-1beta, and IL-7 did not contribute significantly to the IL-12-mediated effect. IL-15 effect on HIV-1 in PBMC was independent of endogenous cytokine production. However, in Kit 225-K6, neutralizing antibodies to IL-7 had a significant effect on HIV-1 expression. These data suggest that IL-2, IL-12, and IL-15 increase HIV-1 replication predominantly through a posttranscriptional mechanism that may be enhanced by endogenous cytokine production.
authors.affiliation: Department of Immunology/Microbiology, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA.
authors.forename: L
authors.initials: L
authors.lastname: Al-Harthi
authors.forename: K A
authors.initials: KA
authors.lastname: Roebuck
authors.forename: A
authors.initials: A
authors.lastname: Landay
mesh_terms: D000914:Antibodies, Viral / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D018664:Interleukin-12 / Q000494:pharmacology*; D019409:Interleukin-15 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000821:virology; D008213:Lymphocyte Activation / Q000187:drug effects; D012091:Repetitive Sequences, Nucleic Acid; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology; D015533:Transcriptional Activation / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000914:Antibodies, Viral; D016207:Cytokines; D004279:DNA, Viral; D019409:Interleukin-15; D007376:Interleukin-2; D018664:Interleukin-12