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    Combination Immune Checkpoint Blockade to Reverse HIV Latency

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    Author
    Van der Sluis, RM; Kumar, NA; Pascoe, RD; Zerbato, JM; Evans, VA; Dantanarayana, AI; Anderson, JL; Sekaly, RP; Fromentin, R; Chomont, N; ...
    Date
    2020-03-01
    Source Title
    Journal of Immunology
    Publisher
    AMER ASSOC IMMUNOLOGISTS
    University of Melbourne Author/s
    Evans, Vanessa; Lewin, Sharon; Cameron, Paul; Pascoe, Rachel; Zerbato, Jennifer
    Affiliation
    Doherty Institute
    Microbiology and Immunology
    Metadata
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    Document Type
    Journal Article
    Citations
    Van der Sluis, R. M., Kumar, N. A., Pascoe, R. D., Zerbato, J. M., Evans, V. A., Dantanarayana, A. I., Anderson, J. L., Sekaly, R. P., Fromentin, R., Chomont, N., Cameron, P. U. & Lewin, S. R. (2020). Combination Immune Checkpoint Blockade to Reverse HIV Latency. JOURNAL OF IMMUNOLOGY, 204 (5), pp.1242-1254. https://doi.org/10.4049/jimmunol.1901191.
    Access Status
    Access this item via the Open Access location
    URI
    http://hdl.handle.net/11343/254028
    DOI
    10.4049/jimmunol.1901191
    Open Access URL
    http://europepmc.org/articles/pmc7354848?pdf=render
    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.

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