Cell-specific roles for PERK in HIV-induced neuroinflammation

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

Several risk factors including older age, low nadir CD4+ count, and metabolic syndrome are related to neurocognitive impairment (NCI) and mental health disruption with altered activities of daily living in 15% of people with HIV (PWH) despite effective viral suppression and immune recovery with antiretroviral therapy (ART). Although rapid ART initiation achieves the most beneficial outcomes, a subset of PWH remain at risk for NCI. Identification of predictive markers for NCI are needed not only to recognize those at risk but also to provide therapeutic opportunities for pharmacologic interventions in at-risk populations. We have identified significant associations between the endoplasmic reticulum kinase, PERK, one of the four kinases in the ubiquitous integrated stress response, with NCI in samples from the NNTC. Pathologic evidence indicates increased PERK activity in neurons and astrocytes in autopsy tissue of PWH with NCI. PERK-regulated signaling plays roles in orchestrating responses to protein misfolding, inflammation, oxidative stress, iron regulation, and multiorganellar response, such as those associated with HIV infection in the CNS, Further, PERK contributes to cell fate decisions under such conditions. PERK signaling through phosphorylation of translation initiation factor, eIF2α, and antioxidant response transcriptional regulator, NRF2, are linked to neuronal, astrocytic, and macrophage/microglial function, health, and stress response. Tight regulation of PERK kinase activity to a narrow window is necessary for stress tolerance without pathological effects, wherein constant, low-level, non-lethal ER stress preconditions and provides acquired resilience against endogenous and exogenous stresses by priming downstream signaling cascades such as antioxidant response, autophagy, and iron regulation. Despite its canonical role as a coordinator in mounting stress response involving multiple organelles, much needs to be learned about PERK’s role in cells of the CNS and their contribution to cognitive impairment and mental health disruption, including a) its function in stress tolerance, b) cell type-specific mechanisms modulating PERK activity, c) impact cell type-specific PERK-mediated stress response and stress tolerance, and d) association of PERK expression and activity with specific NC domain deficits and disease progression in PWH. We found i) differential and cell type-specific activity of PERK in primary rodent astrocytes and macrophages compared with neurons, ii) cell type-specific stress tolerance in astrocytes which was not observed in neurons and iii) differential outcomes of cells exhibiting stress tolerance. We posit that differential stress tolerance of PERK in specific cell types contributes to NCI and other CNS phenotypes in PWH. We will use biochemical, cellular, and pharmacologic approaches to assess the potential role of PERK in the development of a mechanistic risk score as a precision medicine tool to identify PWH who may benefit from adjunctive pharmacologic therapies such as modulators of PERK and other mediators of stress tolerance during the best therapeutic window, soon after HIV diagnosis.