Synchronized latency reversal and immune clearance by a multifunctional fusion protein enables HIV-1 reservoir...

Area of Science:

• Immunology
• Virology
• Biotechnology

Background:

• HIV-1 latency establishes persistent viral reservoirs, a major barrier to cure.
• Current antiretroviral therapies control viral replication but do not eliminate latent reservoirs.

Purpose of the Study:

• To develop a single-molecule agent that simultaneously reactivates latent HIV-1 and promotes immune-mediated viral clearance.
• To evaluate the efficacy and safety of hyperIL-15×sCD4-Fc in preclinical models.

Main Methods:

• Development of hyperIL-15×sCD4-Fc, a fusion protein combining IL-15 signaling and sCD4-Fc for HIV-1 envelope engagement.
• Assessment of latency reversal in CD4+ T cells from people living with HIV-1 (PLWH).
• Evaluation of enhanced T cell responses and NK cell-mediated killing of infected cells.
• Quantification of replication-competent HIV-1 DNA reduction in PBMCs and viral reservoir in humanized mice.

Main Results:

• HyperIL-15×sCD4-Fc potently reversed HIV-1 latency and enhanced antigen-specific CD8+ T cell responses.
• The fusion protein facilitated Env-specific elimination of reactivated cells by NK cells with minimal off-target effects.
• A 93.8% reduction in replication-competent HIV-1 DNA was observed in PLWH PBMCs.
• The molecule demonstrated safety and efficacy in reducing the viral reservoir in lymphoid organs of treated humanized mice.

Conclusions:

• HyperIL-15×sCD4-Fc represents a novel, single-molecule strategy for targeting latent HIV-1 reservoirs.
• The combined approach of latency reactivation and immune clearance offers a clinically viable path toward an HIV cure.
• This therapy has the potential to significantly impact the long-term management and potential eradication of HIV-1.