Repurposing Atovaquone for Eliminating HIV-Infected T-Cells

Background & Unmet Need

• Majority of patients with HIV are well-managed on chronic antiretroviral therapy (ART)
• Although ART suppresses HIV replication, it cannot eliminate integrated HIV within infected T cells, which creates a viral reservoir that triggers viral rebound if treatment stops
• Latency reversal agents (LRAs) intended to reactivate latent HIV have proven ineffective in reducing the viral reservoir despite enabling ART and immune recognition
• Persistence of HIV reservoirs are not only due to latency but also selection for infected cells that are resistant to killing
• Unmet Need: Therapy that effectively eliminates persistently infected HIV cells to achieve viral eradication

Technology Overview

• The Technology: Repurposing of Atovaquone (ATQ), as a treatment strategy for eliminating HIV viral reservoir
• The Discovery: HIV-infected CD4+ T-cells resistant to cytotoxic T-lymphocytes (CTL) have lower expression of gene-sets defining active metabolism and oxidative stress​
• These cells have lower levels of intracellular ROS, making them more susceptible to agents that induce oxidative stress (e.g., ROS inducers)
• PoC Data: ATQ induces oxidative stress on human CD4+ T cells​
• ATQ sensitizes infected CD4+ T-cells from multiple donors to CTL-mediated killing
• Currently evaluating effectiveness of ATQ in mouse models using patient-derive xenografts models of HIV infection

Technology Applications

• Complement existing ART, to clear HIV-positive T cells towards a functional or absolute "cure”
• Alone or in combination with other therapeutic agents, providing a new approach to managing HIV infections

Technology Advantages

• ATQ is an established and well-tolerated drug
• Serve a dual purpose, treating both latent reservoirs and protozoal infections in HIV patients
• Existing manufacturing processes and availability make ATQ a cost-effective option compared to newer, more specialized drugs

Figure 1: CD4+ T cells infected with wild-type HIV have a lower survival rate when pre-treated with ATQ (pre-ATO WT Survivor) compared to those that weren’t (DMSO WT Survivor)