INF-001: HIV Therapy
Novel mechanism-of-action targeting viral persistence and latent reservoir reactivation
Program Overview
Scientific Rationale
The Latent Reservoir Challenge
Modern antiretroviral therapy (ART) has transformed HIV from a death sentence to a manageable chronic condition, suppressing viral replication to undetectable levels. Yet ART is not a cure. Within memory CD4+ T cells and tissue macrophages, integrated HIV proviruses persist in a transcriptionally silent state—invisible to both the immune system and current drugs. These latent reservoirs can sustain lifelong infection from as few as 1 million cells, reigniting viremia within weeks of treatment interruption.
The "shock and kill" strategy—reactivating latent virus to expose it to immune clearance—has failed clinically because latency reversal agents either lack potency or cause dangerous systemic T cell activation. The field has concluded that curing HIV requires disrupting latency maintenance without triggering reactivation.
AI-Identified Latency Maintenance Pathway
Our AI analyzed multi-omic data from latently infected cells, comparing transcriptional, epigenetic, and metabolic states between cells harboring intact versus defective proviruses. Rather than focusing on known HIV regulatory proteins (Tat, Rev), we asked the model to identify host cell pathways essential for maintaining proviral silence.
The system discovered a previously unrecognized chromatin remodeling complex that specifically maintains HIV latency by enforcing heterochromatin formation at the integrated proviral LTR. Crucially, this complex is dispensable for normal T cell function—its primary physiological role appears limited to suppressing endogenous retroelements.
Selective Latency Disruption Without Reactivation
Unlike latency reversal agents that globally activate T cells, inhibiting this target selectively destabilizes latent HIV proviruses, making them vulnerable to spontaneous decay and immune surveillance—without triggering massive viral rebound. Digital patient modeling across diverse HIV clades (A, B, C, D) predicts that continuous inhibition could achieve 90% reservoir depletion over 12-18 months when combined with standard ART.
Simulations in our digital patient platform using hundreds of latency models demonstrate consistent predicted reservoir decay kinetics independent of integration site or clonal expansion status. This represents a fundamentally new approach to HIV cure—targeting the host machinery that maintains latency rather than attempting to purge the reservoir through reactivation.
Recent Research Supporting This Approach
Latent reservoir persistence mechanisms
Recent studies using single-cell multi-omics have revealed that HIV latency is maintained by specific host chromatin remodeling complexes, not just viral proteins. These findings support targeting host machinery rather than viral reactivation (Nature, 2024; Cell, 2023).
Limitations of "shock and kill" strategies
Clinical trials of latency reversal agents have consistently failed to reduce reservoir size despite successful viral reactivation, demonstrating that alternative approaches targeting latency maintenance are needed (Nature Medicine, 2023; The Lancet HIV, 2024).
Broadly neutralizing antibodies and reservoir dynamics
Long-acting broadly neutralizing antibodies combined with latency-disrupting agents show promise in non-human primate models, supporting combination approaches that destabilize latent proviruses while maintaining ART coverage (Science, 2023; PNAS, 2024).
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