ABSTRACT
Human neurotropic immunodeficiency virus (HIV) ingress into the brain and its subsequent replication after infection results in viral reservoirs in the brain. The infected cells include microglia, perivascular macrophages, and astrocytes. HIV-associated neurocognitive disorders (HAND) affect glial cells by activating microglia and macrophages through neuroinflammation, as well as astrocytes through mitochondrial dysfunctions and the onset of oxidative stress, impairing the ability of these cells to engage in neuroprotection. Furthermore, the risk of neuroinflammation associated with HAND is magnified by recreational drug use in HIV-positive individuals. Most of the therapeutic options for HIV cannot be used to tackle the virus in the brain and treat HAND due to the inability of currently available combination antiretroviral therapies (ARTs) and neuroprotectants to cross the blood-brain barrier, even if the barrier is partially compromised by infection. Here, we report a strategy to deliver an optimized antiretroviral therapy combined with antioxidant and anti-inflammatory neuroprotectants using biodegradable brain-targeted polymeric nanoparticles to reduce the burden caused by viral reservoirs in the brain and tackle the oxidative stress and inflammation in astrocytes and microglia. Through in vitro coculture studies in human microglia and astrocytes as well as an in vivo efficacy study in an EcoHIV-infected, methamphetamine-exposed animal model, we established a nanoparticle-based therapeutic strategy with the ability to treat HIV infection in the central nervous system in conditions simulating drug use while providing enhanced protection to astrocytes, microglia, and neurons.
