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Combination Immune Checkpoint Blockade to Reverse HIV Latency

Renée M. Van der Sluis, Nitasha A. Kumar, Rachel D. Pascoe, Jennifer M. Zerbato, Vanessa A. Evans, Ashanti I. Dantanarayana, Jenny L. Anderson, Rafick P. Sékaly, Rémi Fromentin, Nicolas Chomont, Paul U. Cameron and Sharon R. Lewin
J Immunol January 27, 2020, ji1901191; DOI: https://doi.org/10.4049/jimmunol.1901191
Renée M. Van der Sluis
*The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria 3000, Australia;
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Nitasha A. Kumar
*The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria 3000, Australia;
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Rachel D. Pascoe
*The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria 3000, Australia;
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Jennifer M. Zerbato
*The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria 3000, Australia;
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Vanessa A. Evans
*The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria 3000, Australia;
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Ashanti I. Dantanarayana
*The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria 3000, Australia;
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Jenny L. Anderson
*The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria 3000, Australia;
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Rafick P. Sékaly
†Case Western Reserve University, Cleveland, OH 44106;
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Rémi Fromentin
‡Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, Quebec H2X 3E4, Canada;
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Nicolas Chomont
‡Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, Quebec H2X 3E4, Canada;
§Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, Université de Montréal, Montreal, Quebec H3T 1J4, Canada; and
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Paul U. Cameron
*The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria 3000, Australia;
¶Department of Infectious Diseases, Monash University and the Alfred Hospital, Melbourne, Victoria 3000, Australia
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Sharon R. Lewin
*The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria 3000, Australia;
¶Department of Infectious Diseases, Monash University and the Alfred Hospital, Melbourne, Victoria 3000, Australia
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Key Points

  • Blocking CTLA-4 or PD-1 combined with T cell activation reverses HIV latency.

  • Without T cell activation, blocking multiple ICs reverses latency.

Abstract

In people living with HIV on antiretroviral therapy, HIV latency is the major barrier to a cure. HIV persists preferentially in CD4+ T cells expressing multiple immune checkpoint (IC) molecules, including programmed death (PD)-1, T cell Ig and mucin domain-containing protein 3 (TIM-3), lymphocyte associated gene 3 (LAG-3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT). We aimed to determine whether these and other IC molecules have a functional role in maintaining HIV latency and whether blocking IC molecules with Abs reverses HIV latency. Using an in vitro model that establishes latency in both nonproliferating and proliferating human CD4+ T cells, we show that proliferating cells express multiple IC molecules at high levels. Latent infection was enriched in proliferating cells expressing PD-1. In contrast, nonproliferating cells expressed IC molecules at significantly lower levels, but latent infection was enriched in cells expressing PD-1, TIM-3, CTL-associated protein 4 (CTLA-4), or B and T lymphocyte attenuator (BTLA). In the presence of an additional T cell–activating stimulus, staphylococcal enterotoxin B, Abs to CTLA-4 and PD-1 reversed HIV latency in proliferating and nonproliferating CD4+ T cells, respectively. In the absence of staphylococcal enterotoxin B, only the combination of Abs to PD-1, CTLA-4, TIM-3, and TIGIT reversed latency. The potency of latency reversal was significantly higher following combination IC blockade compared with other latency-reversing agents, including vorinostat and bryostatin. Combination IC blockade should be further explored as a strategy to reverse HIV latency.

Footnotes

  • This work was supported by funds from The Foundation for AIDS Research (Grants 108237-51-RGRL and 109226-58-RGRL), the National Health and Medical Research Council (NHMRC) of Australia (Grants APP1041795 and APP3162044), and the National Institutes of Health Delaney AIDS Research Enterprise to Find a Cure Collaboratory (Grant UM1AI126611-01). S.R.L. is an NHMRC Practitioner Fellow.

  • The online version of this article contains supplemental material.

  • Received October 1, 2019.
  • Accepted December 18, 2019.
  • Copyright © 2020 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 209 (1)
The Journal of Immunology
Vol. 209, Issue 1
1 Jul 2022
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Combination Immune Checkpoint Blockade to Reverse HIV Latency
Renée M. Van der Sluis, Nitasha A. Kumar, Rachel D. Pascoe, Jennifer M. Zerbato, Vanessa A. Evans, Ashanti I. Dantanarayana, Jenny L. Anderson, Rafick P. Sékaly, Rémi Fromentin, Nicolas Chomont, Paul U. Cameron, Sharon R. Lewin
The Journal of Immunology January 27, 2020, ji1901191; DOI: 10.4049/jimmunol.1901191

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Combination Immune Checkpoint Blockade to Reverse HIV Latency
Renée M. Van der Sluis, Nitasha A. Kumar, Rachel D. Pascoe, Jennifer M. Zerbato, Vanessa A. Evans, Ashanti I. Dantanarayana, Jenny L. Anderson, Rafick P. Sékaly, Rémi Fromentin, Nicolas Chomont, Paul U. Cameron, Sharon R. Lewin
The Journal of Immunology January 27, 2020, ji1901191; DOI: 10.4049/jimmunol.1901191
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