Evidence Audit: An Unresolved Therapeutic-Window Question in Redox Sensitization of CTL-Resistant HIV Reservoir Cells

Nature of this document: This is an Evidence Audit based on published literature. It contains no new experimental data. It does not claim efficacy or safety for any therapy. Its purpose is to identify an unresolved comparative gap in an existing research direction. A subset of persistent HIV reservoir cells displays cell-intrinsic resistance to cytotoxic T lymphocyte (CTL)-mediated killing. In authentic reservoir clone (ARC) studies, low oxidative stress was linked to CTL resistance, and deferoxamine (DFO) enhanced CTL-mediated elimination of a resistant clone. Related multi-omic work (preprint) found that HIV-infected CD4 T cells surviving CTL attack were enriched for metabolically quiescent, low-ROS states and could be sensitized to CTL killing by DFO. Independent work has also linked HIV latency to glycolytic downregulation and redox dependency. The effector arm, however, may itself be redox-sensitive. In chronic LCMV infection, virus-specific exhausted CD8 T cells exhibit lipid-peroxidation accumulation, impaired GPX4 expression and activity, and ferroptosis-associated clonal loss. In chronic human HBV infection, HBV-specific CD8 T cells likewise show ferroptosis-associated dysfunction and reduced GPX4. In the targeted search performed for this audit, no study was identified that directly establishes an equivalent ferroptotic vulnerability in HIV-specific CD8 T cells, or that directly compares HIV reservoir-bearing CD4 cells and HIV-specific CD8 cells under the same redox-sensitizing exposure. Accordingly, the relevant question is not whether reservoir cells can be redox-sensitized in isolation, but whether a usable differential window exists between target-cell sensitization and effector-cell impairment. This requirement is stated for broad pro-oxidant or redox-sensitizing exposures; DFO monotherapy is treated separately, because DFO acts as a ferroptosis inhibitor in other experimental systems and also stabilizes HIF, so its net directional effect on the effector arm is regarded as undetermined within the scope of this audit. Conclusion: Redox vulnerability on the reservoir side is directly supported, whereas the corresponding redox tolerance of the HIV-specific effector arm is not established. This is not a therapeutic proposal. It is a measurement gap that should be resolved before redox-based reservoir elimination is evaluated as a treatment direction.