the role of lipids in the pathogenesis of neuroHIV

A critical comorbidity of HIV infection is HIV-associated neurocognitive disorders (HAND). Although combined antiretroviral therapy (cART) is an effective treatment in blocking systemic viral replication, it is unsuccessful in reducing the incidence of HAND. HIV CNS damage, in the current cART era, can be associated to the presence of latently HIV-infected cells including microglia/macrophages and a small population of astrocytes. This Ph.D. thesis focuses on identifying, localizing, and quantifying viral reservoirs using an improved staining and microscopy technique. Although in low amount, our data confirmed that microglia/macrophages and a small population of astrocytes are still infected. These cells synthetize and secrete viral proteins generating a bystander damage in the CNS. Viral proteins are also involved in lipid dysregulation. We demonstrated by Mass Spectrometry Imaging (MSI) that in the brain of HIV-infected individuals with HAND lipids including sulfatide play a key role in bystander damage. Sulfatide is dysregulated in several neurocognitive diseases such as Alzheimer’s disease and Parkinson’s disease. Thus, we propose that sulfatide as a potential biomarker of neurocognitive disorders. We demonstrated that sulfatide secretion can be regulated by HIV proteins and we evaluated sulfatide effects in vitro, focusing on cell-to-cell communication and mitochondrial metabolism, all parameters altered in NeuroHIV. Therefore, this thesis provides specific tools and unique data to a better understanding the neuropathogenesis of HAND in the current cART-era and may lead to the identification of new molecular targets for preventing or curing HIV neurological decline.