SARS CoV-2 mRNA vaccination exposes latent HIV to Nef-specific CD8 T-cells

Eva M. Stevenson, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Sandra Terry, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Dennis Copertino, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Louise Leyre, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Ali Danesh, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Jared Weiler, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Adam R. Ward, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Pragya Khadka, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Evan McNeil, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Kevin Bernard, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Itzayana G. Miller, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Grant B. Ellsworth, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Carrie D. Johnston, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Eli J. Finkelsztein, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Paul Zumbo, Applied Bioinformatics Core, Weill Cornell Medical College, New York, NY, USA.
Doron Betel, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Friederike Dündar, Applied Bioinformatics Core, Weill Cornell Medical College, New York, NY, USA.
Maggie C. Duncan, Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada.
Hope R. Lapointe, British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada.
Sarah Speckmaier, British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada.
Nadia Moran-Garcia, British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada.
Michelle Premazzi Papa, Dept of Microbiology Immunology and Tropical Medicine, The George Washington University, Washington, DC, USA.
Samuel Nicholes, Dept of Microbiology Immunology and Tropical Medicine, The George Washington University, Washington, DC, USA.
Carissa J. Stover, Dept of Microbiology Immunology and Tropical Medicine, The George Washington University, Washington, DC, USA.
Rebecca M. Lynch, Dept of Microbiology Immunology and Tropical Medicine, The George Washington University, Washington, DC, USA.
Marina Caskey, Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA.
Christian Gaebler, Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA.
Tae-Wook Chun, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID, NIH, Bethesda, MD, USA.
Alberto Bosque, Dept of Microbiology Immunology and Tropical Medicine, The George Washington University, Washington, DC, USA.
Timothy J. Wilkin, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Guinevere Q. Lee, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Zabrina L. Brumme, Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada.

Document Type

Journal Article

Publication Date

8-19-2022

Journal

Nature communications

Volume

13

Issue

1

DOI

10.1038/s41467-022-32376-z

Abstract

Efforts to cure HIV have focused on reactivating latent proviruses to enable elimination by CD8 cytotoxic T-cells. Clinical studies of latency reversing agents (LRA) in antiretroviral therapy (ART)-treated individuals have shown increases in HIV transcription, but without reductions in virologic measures, or evidence that HIV-specific CD8 T-cells were productively engaged. Here, we show that the SARS-CoV-2 mRNA vaccine BNT162b2 activates the RIG-I/TLR - TNF - NFκb axis, resulting in transcription of HIV proviruses with minimal perturbations of T-cell activation and host transcription. T-cells specific for the early gene-product HIV-Nef uniquely increased in frequency and acquired effector function (granzyme-B) in ART-treated individuals following SARS-CoV-2 mRNA vaccination. These parameters of CD8 T-cell induction correlated with significant decreases in cell-associated HIV mRNA, suggesting killing or suppression of cells transcribing HIV. Thus, we report the observation of an intervention-induced reduction in a measure of HIV persistence, accompanied by precise immune correlates, in ART-suppressed individuals. However, we did not observe significant depletions of intact proviruses, underscoring challenges to achieving (or measuring) HIV reservoir reductions. Overall, our results support prioritizing the measurement of granzyme-B-producing Nef-specific responses in latency reversal studies and add impetus to developing HIV-targeted mRNA therapeutic vaccines that leverage built-in LRA activity.

Department

Microbiology, Immunology, and Tropical Medicine

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