Combination Immune Checkpoint Blockade to Reverse HIV Latency.

Area of Science:

• Immunology
• Virology
• Cell Biology

Background:

• HIV latency in CD4+ T cells is a significant obstacle to curing HIV, even with antiretroviral therapy.
• HIV preferentially persists in CD4+ T cells expressing multiple immune checkpoint (IC) molecules like PD-1, TIM-3, LAG-3, and TIGIT.

Purpose of the Study:

• To investigate the functional role of IC molecules in maintaining HIV latency.
• To determine if blocking IC molecules with antibodies can reverse HIV latency.

Main Methods:

• Utilized an in vitro model to establish HIV latency in both nonproliferating and proliferating human CD4+ T cells.
• Analyzed the expression levels of various IC molecules on latently infected cells.
• Tested the efficacy of blocking individual IC molecules and combinations thereof in reversing latency, with and without T cell activation.

Main Results:

• Proliferating CD4+ T cells expressed higher levels of multiple IC molecules, with latent HIV enriched in PD-1 expressing cells.
• Nonproliferating cells showed lower IC molecule expression, but latency was enriched in cells expressing PD-1, TIM-3, CTLA-4, or BTLA.
• Antibodies targeting CTLA-4 and PD-1 reversed latency in proliferating and nonproliferating cells, respectively, with an activating stimulus.
• A combination of antibodies against PD-1, CTLA-4, TIM-3, and TIGIT reversed latency without an activating stimulus.
• Combination IC blockade demonstrated significantly higher potency in reversing latency compared to vorinostat and bryostatin.

Conclusions:

• Immune checkpoint molecules play a crucial role in maintaining HIV latency.
• Combination blockade of IC molecules is a highly effective strategy for reversing HIV latency.
• Further research into combination IC blockade is warranted as a potential HIV cure strategy.