Activating PKC-ε induces HIV expression with improved tolerability

Area of Science:

• Virology
• Immunology
• Pharmacology

Background:

• HIV-1 establishes latent reservoirs despite antiretroviral therapy (ART), necessitating lifelong treatment.
• Activating latent HIV during ART could enhance immune-mediated elimination of infected cells.
• Protein kinase C (PKC) isozymes can increase HIV transcription, making them potential latency-reversing agents.

Purpose of the Study:

• To investigate the toxicity of PKC activation and develop selective PKC agonists for safe HIV latency reversal.
• To identify PKC isoforms involved in T-cell activation and potential off-target effects.

Main Methods:

• Ex vivo treatment of CD4+ T cells from people with HIV with PKC agonists.
• Structure-based drug design to create a novel, selective PKC agonist (C-233).
• Assessment of T-cell and platelet activation, HIV RNA, and p24 expression.

Main Results:

• PKC activation caused significant platelet activation and signs of disseminated intravascular coagulation at T-cell activating concentrations.
• PKC-ε and PKC-η isoforms are highly expressed in CD4+ T cells but not platelets.
• The novel agonist C-233 selectively activated PKC-ε, demonstrating 5-fold greater potency for T-cell activation versus platelet activation.
• C-233 increased HIV RNA and p24 expression in CD4+ T cells ex vivo.

Conclusions:

• Structure-based drug design can yield selective PKC agonists with improved safety profiles.
• Selective PKC agonists, like C-233, offer a promising strategy for safe HIV latency reversal.
• Targeted activation of HIV reservoirs may enhance tolerability and efficacy of HIV cure strategies.