Human immunodeficiency virus (HIV) is known primarily for its impact on the immune system, but other organ systems are also affected in People with HIV (PWH). The effects of HIV on the central nervous system often lead to neurocognitive dysfunction, known as HIV-associated neurocognitive disorders (HAND). The introduction of combined antiretroviral therapy (cART), resulted in a significant decrease in death of PWH as well as a decrease in the most severe form of HAND. However, approximately 50% of PWH still experience symptoms of HAND. White matter abnormalities such as thinning of the corpus collosum and loss of volume and structural integrity have been observed in PWH with HAND, with more severe cognitive impairment correlating to amount of white matter damage. White matter is made up mostly of myelin which is produced by mature oligodendrocytes.  Our lab has previously established that several ART medications such as elvitegravir impede oligodendrocyte maturation both in vitro and in vivo and have implicated several cellular mechanisms in this inhibition. One of these is the activation of the integrated stress response (ISR). 

The ISR can be activated through four kinases in response to stressors; GCN2 (amino acid deprivation), PKR (viral infection), HRI (heme deprivation) and PERK (ER stress). Endoplasmic reticular (ER) stress, which activates the protein kinase, PERK, is of particular interest. Previous studies have implicated PERK in neurodegenerative and demyelinating disease. Our lab also demonstrated that cells treated with the antiretroviral drug, elvitegravir, activate the ISR through PERK, which in turn inhibits maturation. ISR activation can lead to the formation of stress granules (SGs), which are membraneless cytoplasmic condensates of messenger ribonucleoproteins (mRNPs) and mRNA-binding proteins, thought to aid in ISR-mediated cellular recovery by temporarily sequestering mRNAs. When chronically induced, however, SGs may be pathologic, and have been implicated in a number of neurodegenerative diseases. We have previously established that SGs form through ISR activation in partially differentiated oligodendrocytes acutely treated with elvitegravir. Therefore, the current aim is to understand which ISR pathway is implicated in SG formation.

We hypothesize that the stress granules observed in oligodendrocytes treated acutely with dolutegravir and elvitegravir form through the PERK activated ISR.