Multimeric immunotherapeutic complexes activating natural killer cells towards HIV-1 cure

Area of Science:

• Immunology
• Virology
• Therapeutics

Background:

• Combination antiretroviral therapy (cART) controls HIV-1 but does not eliminate viral reservoirs.
• HIV-1 infection reduces cytotoxic natural killer (NK) cells, which express checkpoint inhibitors like NKG2A and KIR2DL.
• NK cells expressing CXCR5 are crucial for controlling HIV-1 replication.

Purpose of the Study:

• To design and evaluate Natural killer activating Multimeric immunotherapeutic compleXes (NaMiX) for killing HIV-1 infected cells.
• To assess NaMiX's efficacy in vitro and in humanized mouse models.
• To investigate NaMiX's potential as a supportive strategy for HIV-1 cure.

Main Methods:

• NaMiX developed by combining IL-15/IL-15Rα multimers with anti-NKG2A or anti-KIR single-chain fragment variable (scFv).
• NaMiX entities were multimerized into heptamer (α) or dimer (β) forms.
• Evaluated in vitro models and humanized NSG tg-huIL-15 mice.

Main Results:

• NaMiX enhanced NK and CD8+ T cell cytolytic activity, degranulation, and cytokine release against HIV-1 infected cells.
• Anti-NKG2A NaMiX demonstrated stronger effects than anti-KIR NaMiX.
• In HIV-1 positive individuals, anti-NKG2A NaMiX enhanced NK cell activation, cytotoxicity, IFN-γ production, and CXCR5 expression.
• In humanized mice, anti-NKG2A.α NaMiX improved NK cell functions and reduced viral DNA.

Conclusions:

• NaMiX, particularly anti-NKG2A.α, enhances NK cell-mediated killing of HIV-1 infected cells.
• This approach shows potential for supporting HIV-1 cure strategies.
• NaMiX represents a promising immunotherapy for HIV-1 treatment.