Advancements in HIV-1 cure strategies:Combining agents to reverse viral latency and shape antiviral immunity

This work investigates how innate immune mechanisms can be harnessed for antiviral intervention, spanning mucosal prophylaxis against SARS-CoV-2 and immunomodulatory strategies relevant to HIV-1 cure. We outline key principles of innate sensing and the rationale for targeting early viral entry and pattern-recognition receptor (PRR) pathways. Subsequently we demonstrate that low-molecular-weight heparin can act as a decoy for heparan sulfate–dependent SARS-CoV-2 attachment, supporting inhaled prophylaxis as a practical entry-blocking approach. We evaluate aerosol delivery of fragile biologics and shows that nebulization energy is a critical determinant of lipid nanoparticle and mRNA integrity, with low-energy aerosolization preserving functional stability. Shifting to immunomodulation, we summarize current knowledge on PRR crosstalk as a mechanism that tailors antiviral programs, providing a conceptual framework for subsequent chapters. Building on this, we show that coordinated stimulation of TLR8 and RIG-I–like receptors can synergistically enhance antiviral cytokine profiles and interferon-stimulated gene programs. We extend these observations to clinical cohorts, indicating that monocyte functionality is only transiently preserved following HIV infection and diminishes following long-term suppressive therapy. We evaluate combination approaches that couple innate agonists with a SMAC mimetic, enhancing TLR8-driven immune activation and supporting reductions in inducible HIV-1 reservoir ex vivo. Last, we assess TLR4-targeted adjuvants (MPLA and SMNP), demonstrating robust innate activation and cytokine-mediated, indirect HIV-1 latency reversal, with evidence for effects on reservoir measurements without overt bystander cytotoxicity. Finally we integrate these findings and discusses translational opportunities and constraints for safe, timing-sensitive immunomodulatory interventions.