title: HIV infection of primary human T cells is determined by tunable thresholds of T cell activation.
abstract: HIV infection of primary human T cells requires T cell activation signals. However, how strength, duration, and quality of TCR signals affect susceptibility of resting human T cells to HIV infection remains poorly understood. We found that the same threshold and duration of antigen signals that lead to optimal T cell activation are required for HIV to progress beyond the level of reverse transcription within resting T cells. Remarkably, sustained cytokine signaling from the IL-2 receptor following TCR triggering was critical in establishing productive infection. While blockade of TCR signaling pathways with inhibitors of the phosphatidylinositol 3-kinase pathway caused a partial pre-integration block, another inhibitor, rapamycin, completely suppressed the infection. In contrast, cyclosporin A or FK506, inhibitors of NFAT, failed to block infection if the T cells were pre-activated. Collectively, these results bring to light significant parallels between successful HIV infection and optimal thresholds of T cell activation. Furthermore, our results underscore the critical role of IL-2 signaling in establishing productive HIV infection. These findings have important implications for our understanding of the complex interplay of HIV with host factors induced upon T cell activation.
authors.affiliation: Department of Microbiology and Immunology, Vanderbilt University Medical School, Nashville, TN 37232, USA.
authors.forename: Kyra
authors.initials: K
authors.lastname: Oswald-Richter
authors.forename: Stacy M
authors.initials: SM
authors.lastname: Grill
authors.forename: Mindy
authors.initials: M
authors.lastname: Leelawong
authors.forename: Derya
authors.initials: D
authors.lastname: Unutmaz
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000821:virology*; D002455:Cell Division / Q000276:immunology; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000276:immunology; D006678:HIV / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D007700:Kinetics; D008213:Lymphocyte Activation / Q000276:immunology; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D012194:RNA-Directed DNA Polymerase / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000276:immunology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D020123:Sirolimus / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology; D014157:Transcription Factors / Q000276:immunology; D014779:Virus Replication / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D018894:Reverse Transcriptase Inhibitors; D014157:Transcription Factors; D016572:Cyclosporine; D012194:RNA-Directed DNA Polymerase; D020123:Sirolimus; D016559:Tacrolimus