title: Blood-Derived CD4 T Cells Naturally Resist Pyroptosis during Abortive HIV-1 Infection.
abstract: Progression to AIDS is driven by CD4 T cell depletion, mostly involving pyroptosis elicited by abortive HIV infection of CD4 T cells in lymphoid tissues. Inefficient reverse transcription in these cells leads to cytoplasmic accumulation of viral DNAs that are detected by the DNA sensor IFI16, resulting in inflammasome assembly, caspase-1 activation, and pyroptosis. Unexpectedly, we found that peripheral blood-derived CD4 T cells naturally resist pyroptosis. This resistance is partly due to their deeper resting state, resulting in fewer HIV-1 reverse transcripts and lower IFI16 expression. However, when co-cultured with lymphoid-derived cells, blood-derived CD4 T cells become sensitized to pyroptosis, likely recapitulating interactions occurring within lymphoid tissues. Sensitization correlates with higher levels of activated NF-κB, IFI16 expression, and reverse transcription. Blood-derived lymphocytes purified from co-cultures lose sensitivity to pyroptosis. These differences highlight how the lymphoid tissue microenvironment encountered by trafficking CD4 T lymphocytes dynamically shapes their biological response to HIV.
authors.affiliation: School of Public Health, Division of Infectious Diseases and Virology, University of California, Berkeley, Berkeley, CA 94720, USA; Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, CA 94158, USA.
authors.forename: Isa
authors.initials: I
authors.lastname: Muñoz-Arias
authors.affiliation: Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, CA 94158, USA.
authors.forename: Gilad
authors.initials: G
authors.lastname: Doitsh
authors.affiliation: Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, CA 94158, USA.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, CA 94158, USA.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Sowinski
authors.affiliation: Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, CA 94158, USA.
authors.forename: Debbie
authors.initials: D
authors.lastname: Ruelas
authors.affiliation: Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: wgreene@gladstone.ucsf.edu.
authors.forename: Warner C
authors.initials: WC
authors.lastname: Greene
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000821:virology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D015870:Gene Expression; D015497:HIV-1 / Q000254:growth & development*; D006801:Humans; D016328:NF-kappa B / Q000096:biosynthesis; D009687:Nuclear Proteins / Q000096:biosynthesis; D010750:Phosphoproteins / Q000096:biosynthesis; D000069292:Pyroptosis; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016328:NF-kappa B; D009687:Nuclear Proteins; D010750:Phosphoproteins; C076700:IFI16 protein, human