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Combination Immune Checkpoint Blockade to Reverse HIV Latency

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  • Renée M Van der Sluis
  • Nitasha A Kumar, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria, 3000, Australia.
  • ,
  • Rachel D Pascoe, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria, 3000, Australia.
  • ,
  • Jennifer M Zerbato, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria, 3000, Australia.
  • ,
  • Vanessa A Evans, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria, 3000, Australia.
  • ,
  • Ashanti I Dantanarayana, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria, 3000, Australia.
  • ,
  • Jenny L Anderson, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria, 3000, Australia.
  • ,
  • Rafick P Sékaly, Department of Astronomy, Case Western Reserve University, Cleveland, OH 44106-7215, USA
  • ,
  • Rémi Fromentin, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H2X 3E4, Canada.
  • ,
  • Nicolas Chomont, Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, Université de Montréal, Montreal, Quebec H3T 1J4, Canada; and.
  • ,
  • Paul U Cameron, Department of Infectious Diseases, Monash University and the Alfred Hospital, Melbourne, Victoria 3000, Australia.
  • ,
  • Sharon R Lewin, Department of Infectious Diseases, Monash University and the Alfred Hospital, Melbourne, Victoria 3000, Australia.

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.

OriginalsprogEngelsk
TidsskriftJournal of Immunology
Vol/bind204
Nummer5
Sider (fra-til)1242-1254
Antal sider13
ISSN0022-1767
DOI
StatusUdgivet - 1 mar. 2020
Eksternt udgivetJa

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