Combination Immune Checkpoint Blockade to Reverse HIV Latency

J Immunol. 2020 Mar 1;204(5):1242-1254. doi: 10.4049/jimmunol.1901191. Epub 2020 Jan 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal, Murine-Derived / pharmacology*
  • Antigens, CD / immunology
  • CD4-Positive T-Lymphocytes* / immunology
  • CD4-Positive T-Lymphocytes* / pathology
  • CD4-Positive T-Lymphocytes* / virology
  • Cell Proliferation / drug effects*
  • Enterotoxins / pharmacology*
  • Female
  • HEK293 Cells
  • HIV-1 / physiology*
  • Hepatitis A Virus Cellular Receptor 2 / antagonists & inhibitors
  • Hepatitis A Virus Cellular Receptor 2 / immunology
  • Humans
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation Gene 3 Protein
  • Male
  • Models, Immunological*
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology
  • Receptors, Immunologic / antagonists & inhibitors
  • Receptors, Immunologic / immunology
  • Virus Latency* / drug effects
  • Virus Latency* / immunology


  • Antibodies, Monoclonal, Murine-Derived
  • Antigens, CD
  • Enterotoxins
  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Immunologic
  • TIGIT protein, human
  • enterotoxin B, staphylococcal
  • Lymphocyte Activation Gene 3 Protein