HIV-Associated Neurocognitive Disorders: Role of Viral Reservoirs and Lipid Dysregulation

HIV infection has become a chronic and manageable disease due to the effective use of combined anti-retroviral therapies (cART). However, several chronic aging-related comorbidities, including HIV-associated neurocognitive disorders (HAND), persist in the HIV-infected population; but the mechanisms are unknown. We hypothesized that neurocognitive decline in the HIV-infected population is dependent on CNS viral reservoirs by mechanisms of damage amplification mediated by host lipids. HIV CNS damage, in the current cART era, is mediated by a low number of HIV DNA positive macrophages/microglia and astrocytes that support a residual viral mRNA and protein synthesis. Some HIV proteins are secreted and taken into the neighboring uninfected cells, generating bystander damage in the CNS. Viral reservoirs are associated with local myelin structure compromise resulting in the release of several myelin components, including the lipid sulfatide. Soluble sulfatide compromises gap junctional communication and calcium waves, which contribute to the amplification of CNS damage and cognitive impairment that distress the HIV-infected population. Our pending experiments aim to categorize Cx43 interacting proteins after sulfatide treatment by proteomics, to identify specific astrocyte populations that become susceptible to HIV infection or bystander damage by single-cell RNA sequencing, and detect lipid dysregulation in primary human cultures of HIV-infected astrocytes using MALDI-MSI or MALDI-2 MSI. To further examine lipid dysregulation, we also developed a MALDI-2 MSI method to detect lipid classes and species that are not detected with regular MALDI-MSI, using the brain tissue sections of the AD 3xTg mouse model. We proved that this assessment is compatible with subsequent immunofluorescence and histological analyses in the same tissue section. This approach is innovative and helpful in performing a multi-omics characterization for several pathologies, including HAND.