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CD8+ T cells control SIV infection using both cytolytic effects and non-cytolytic suppression of virus production

Author

Listed:
  • Benjamin B. Policicchio

    (University of Pittsburgh)

  • Erwing Fabian Cardozo-Ojeda

    (Fred Hutchinson Cancer Research Center)

  • Cuiling Xu

    (University of Pittsburgh)

  • Dongzhu Ma

    (University of Pittsburgh)

  • Tianyu He

    (University of Pittsburgh)

  • Kevin D. Raehtz

    (University of Pittsburgh)

  • Ranjit Sivanandham

    (University of Pittsburgh)

  • Adam J. Kleinman

    (University of Pittsburgh)

  • Alan S. Perelson

    (Los Alamos National Laboratory)

  • Cristian Apetrei

    (University of Pittsburgh
    University of Pittsburgh)

  • Ivona Pandrea

    (University of Pittsburgh
    University of Pittsburgh)

  • Ruy M. Ribeiro

    (Los Alamos National Laboratory
    Faculdade de Medicina da Universidade de Lisboa (previous address))

Abstract

Whether CD8+ T lymphocytes control human immunodeficiency virus infection by cytopathic or non-cytopathic mechanisms is not fully understood. Multiple studies highlighted non-cytopathic effects, but one hypothesis is that cytopathic effects of CD8+ T cells occur before viral production. Here, to examine the role of CD8+ T cells prior to virus production, we treated SIVmac251-infected macaques with an integrase inhibitor combined with a CD8-depleting antibody, or with either reagent alone. We analyzed the ensuing viral dynamics using a mathematical model that included infected cells pre- and post- viral DNA integration to compare different immune effector mechanisms. Macaques receiving the integrase inhibitor alone experienced greater viral load decays, reaching lower nadirs on treatment, than those treated also with the CD8-depleting antibody. Models including CD8+ cell-mediated reduction of viral production (non-cytolytic) were found to best explain the viral profiles across all macaques, in addition an effect in killing infected cells pre-integration (cytolytic) was supported in some of the best models. Our results suggest that CD8+ T cells have both a cytolytic effect on infected cells before viral integration, and a direct, non-cytolytic effect by suppressing viral production.

Suggested Citation

  • Benjamin B. Policicchio & Erwing Fabian Cardozo-Ojeda & Cuiling Xu & Dongzhu Ma & Tianyu He & Kevin D. Raehtz & Ranjit Sivanandham & Adam J. Kleinman & Alan S. Perelson & Cristian Apetrei & Ivona Pand, 2023. "CD8+ T cells control SIV infection using both cytolytic effects and non-cytolytic suppression of virus production," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42435-8
    DOI: 10.1038/s41467-023-42435-8
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    References listed on IDEAS

    as
    1. E Fabian Cardozo & Adriana Andrade & John W Mellors & Daniel R Kuritzkes & Alan S Perelson & Ruy M Ribeiro, 2017. "Treatment with integrase inhibitor suggests a new interpretation of HIV RNA decay curves that reveals a subset of cells with slow integration," PLOS Pathogens, Public Library of Science, vol. 13(7), pages 1-18, July.
    2. Mario Castro & Rob J de Boer, 2020. "Testing structural identifiability by a simple scaling method," PLOS Computational Biology, Public Library of Science, vol. 16(11), pages 1-15, November.
    3. Kathleen L. Collins & Benjamin K. Chen & Spyros A. Kalams & Bruce D. Walker & David Baltimore, 1998. "HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes," Nature, Nature, vol. 391(6665), pages 397-401, January.
    Full references (including those not matched with items on IDEAS)

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