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

Eva M. Stevenson, Sandra Terry, Dennis Copertino, Louise Leyre, Ali Danesh, Jared Weiler, Adam R. Ward, Pragya Khadka, Evan McNeil, Kevin Bernard, Itzayana G. Miller, Grant B. Ellsworth, Carrie D. Johnston, Eli J. Finkelsztein, Paul Zumbo, Doron Betel, Friederike Dündar, Maggie C. Duncan, Hope R. Lapointe, Sarah Speckmaier, Nadia Moran-Garcia, Michelle Premazzi Papa, Samuel Nicholes, Carissa J. Stover, Rebecca M. Lynch, Marina Caskey, Christian Gaebler, Tae-Wook Chun, Alberto Bosque, Timothy J. Wilkin, Guinevere Q. Lee, Zabrina L. Brumme and R. Brad Jones ()
Additional contact information
Eva M. Stevenson: Weill Cornell Medical College
Sandra Terry: Weill Cornell Medical College
Dennis Copertino: Weill Cornell Medical College
Louise Leyre: Weill Cornell Medical College
Ali Danesh: Weill Cornell Medical College
Jared Weiler: Weill Cornell Medical College
Adam R. Ward: Weill Cornell Medical College
Pragya Khadka: Weill Cornell Medical College
Evan McNeil: Weill Cornell Medical College
Kevin Bernard: Weill Cornell Medical College
Itzayana G. Miller: Weill Cornell Medical College
Grant B. Ellsworth: Weill Cornell Medical College
Carrie D. Johnston: Weill Cornell Medical College
Eli J. Finkelsztein: Weill Cornell Medical College
Paul Zumbo: Weill Cornell Medical College
Doron Betel: Weill Cornell Medical College
Friederike Dündar: Weill Cornell Medical College
Maggie C. Duncan: Simon Fraser University
Hope R. Lapointe: British Columbia Centre for Excellence in HIV/AIDS
Sarah Speckmaier: British Columbia Centre for Excellence in HIV/AIDS
Nadia Moran-Garcia: British Columbia Centre for Excellence in HIV/AIDS
Michelle Premazzi Papa: The George Washington University
Samuel Nicholes: The George Washington University
Carissa J. Stover: The George Washington University
Rebecca M. Lynch: The George Washington University
Marina Caskey: The Rockefeller University
Christian Gaebler: The Rockefeller University
Tae-Wook Chun: National Institute of Allergy and Infectious Diseases (NIAID, NIH
Alberto Bosque: The George Washington University
Timothy J. Wilkin: Weill Cornell Medical College
Guinevere Q. Lee: Weill Cornell Medical College
Zabrina L. Brumme: Simon Fraser University
R. Brad Jones: Weill Cornell Medical College

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32376-z

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