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Author Notes:

Dr. Mirko Paiardini, Email: mirko.paiardini@emory.edu

J.H. contributed to conceptualization, methodology, formal analysis, investigation, writing – original draft, writing – review & editing, and visualization; S.G. contributed to conceptualization, formal analysis, investigation, and writing – original draft; C.N.C. contributed to formal analysis, investigation, and visualization; H.W. contributed to investigation; E.L. contributed to formal analysis and investigation; C.G. contributed to investigation; S.D.F. contributed to methodology and investigation; S.L.M.R. contributed to investigation; J.L.R. contributed to investigation; K.N. contributed to investigation; C.S.M. contributed to conceptualization and investigation; M.N. contributed to investigation; K.B.-S. contributed to investigation; J.S. contributed to formal analysis and investigation; C.K. contributed to investigation; M.P. contributed in investigation; L.M. contributed to investigation; B.C. contributed to investigation; S.J. contributed to investigation; A.S. contributed to investigation; B.J. contributed to resources; A.A.K. contributed to investigation; H.A.-M. contributed to methodology and writing – review & editing; J.L. contributed to methodology and writing – review & editing; D.M.M. contributed to methodology, resources, writing – review & editing, and funding acquisition; G.S. contributed to writing – review & editing and funding acquisition; K.J.B. contributed to methodology, formal analysis, and writing – review & editing; D.F. contributed to conceptualization, methodology, resources, writing – review & editing, supervision, and funding acquisition; J.D.E. contributed to methodology and writing – review & editing; and M.P. contributed to conceptualization, methodology, resources, writing – original draft, writing – review & editing, supervision, and funding acquisition.

We thank S. Ehnert, C. Souder, and E. Strobert (Research Resources and Veterinary Medicine) at YNPRC for providing animal and veterinary care, as well as the Emory Flow Cytometry Core. We thank C. Ashman, G. Jones, L. Anderson, and A. Barnard from GSK for assisting with the preparation and QC of the therapeutic antibodies, as well as K. Fraley, A. Mayer, and G. Page from GSK for measuring antibody and anti-drug antibody levels. We would also like to thank R. Shoemaker, K. Oswald, and W. Bosche at Leidos Biomedical Research for technical assistance. The SIVmac239 strain used to infect the RMs was kindly provided by K. Van Rompay of UC-Davis; anti-Gag tetramers were provided by D. Long at the NIH Tetramer Core Facility at Emory; and ART was supplied through ViiV Healthcare and GSK

The authors declare the following conflict of interest: S.G., C.G. J.S., A.S., B.J., A.A.K., H.A.-M., and D.F. are employed by and/or have financial interests in GlaxoSmithKline or ViiV Healthcare

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Research Funding:

This work was supported by the NIAID, NIH under award numbers R01AI116379 and R21/R33AI116171 to M. Paiardini and by award UM1AI124436 (Emory CIAR). Support for this work was also provided by GlaxoSmithKline and Qura Therapeutics under subcontract 5105399; the Collaboratory of AIDS Researchers for Eradication (CARE; 1UM1AI126619-01) to D. Margolis; the Virology & Drug Discovery Core of Emory CFAR (P30AI050409); ORIP/OD award P51OD011132 (YNPRC) and P51OD011092 (ONPRC); and in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Cell Biology
  • Medicine, Research & Experimental
  • Research & Experimental Medicine

CTLA-4 and PD-1 dual blockade induces SIV reactivation without control of rebound after antiretroviral therapy interruption

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Journal Title:

NATURE MEDICINE

Volume:

Volume 26, Number 4

Publisher:

, Pages 519-+

Type of Work:

Article | Post-print: After Peer Review

Abstract:

The primary human immunodeficiency virus (HIV) reservoir is composed of resting memory CD4+ T cells, which often express the immune checkpoint receptors programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which limit T cell activation via synergistic mechanisms. Using simian immunodeficiency virus (SIV)-infected, long-term antiretroviral therapy (ART)-treated rhesus macaques, we demonstrate that PD-1, CTLA-4 and dual CTLA-4/PD-1 immune checkpoint blockade using monoclonal antibodies is well tolerated, with evidence of bioactivity in blood and lymph nodes. Dual blockade was remarkably more effective than PD-1 blockade alone in enhancing T cell cycling and differentiation, expanding effector-memory T cells and inducing robust viral reactivation in plasma and peripheral blood mononuclear cells. In lymph nodes, dual CTLA-4/PD-1 blockade, but not PD-1 alone, decreased the total and intact SIV-DNA in CD4+ T cells, and SIV-DNA and SIV-RNA in B cell follicles, a major site of viral persistence during ART. None of the tested interventions enhanced SIV-specific CD8+ T cell responses during ART or viral control after ART interruption. Thus, despite CTLA-4/PD-1 blockade inducing robust latency reversal and reducing total levels of integrated virus, the degree of reservoir clearance was still insufficient to achieve viral control. These results suggest that immune checkpoint blockade regimens targeting PD-1 and/or CTLA-4, if performed in people living with HIV with sustained aviremia, are unlikely to induce HIV remission in the absence of additional interventions.
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