RT Journal Article
SR Electronic
T1 Combination Immune Checkpoint Blockade to Reverse HIV Latency
JF The Journal of Immunology
JO J. Immunol.
FD American Association of Immunologists
SP ji1901191
DO 10.4049/jimmunol.1901191
A1 Van der Sluis, Renée M.
A1 Kumar, Nitasha A.
A1 Pascoe, Rachel D.
A1 Zerbato, Jennifer M.
A1 Evans, Vanessa A.
A1 Dantanarayana, Ashanti I.
A1 Anderson, Jenny L.
A1 Sékaly, Rafick P.
A1 Fromentin, Rémi
A1 Chomont, Nicolas
A1 Cameron, Paul U.
A1 Lewin, Sharon R.
YR 2020
UL http://www.jimmunol.org/content/early/2020/01/24/jimmunol.1901191.abstract
AB Blocking CTLA-4 or PD-1 combined with T cell activation reverses HIV latency.Without T cell activation, blocking multiple ICs reverses latency.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.