Effects of HIV and ART on myelination in the adolescent

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Project Summary Adolescents account for a disproportionately high percentage of new HIV infections each year: in 2018, 30% of all new global infections were among 15-25 year-olds, and 21% of all new United States infections were among 13-24 years-olds 2-4. However, we know little about the effects of new infection and therapy on the developing brain in this critical time frame. Limited studies on HIV+ 18-24 year-olds on and off antiretroviral therapy (ART) demonstrate that up to 65% develop behavioral, cognitive and motor impairments meeting the criteria for HIV associated neurocognitive disorder (HAND) 5,6, a proportion higher than that seen in older HIV+ adult counterparts despite lower viremia, higher CD4+ T-cell counts, and shorter durations of infection in adolescents 7. A major gap in our knowledge is the mechanistic basis of this dysfunction in the developing central nervous system (CNS). The effect of virus-mediated and/or ART toxicities on normal myelination and synaptic pruning in the adolescent and young adult brain is unknown. It is well documented that functionally critical development of white matter (WM) and synaptic plasticity continues until the mid-twenties in humans 8. Interestingly, WM deficits, including myelin lesions, decreased myelin sheath thickness, and abnormal myelin protein expression, are among the persistent pathologic findings in HIV+ adults with HAND 1,9-11 Consistent with pathologic findings, transcriptome analyses of cortical gray matter (GM) and WM from HIV+ adults, both ART- naïve and ART-treated, have revealed decreased expression of genes associated with oligodendrocyte (OL) differentiation and myelination 12,13. We have shown HIV-associated neuroinflammation inhibits OL maturation through upregulation of the integrated stress response (a pathway shown to be dysregulated in the CNS of HIV+ patients) 14,15. Further, data from our laboratory also suggest that a subset of ARV drugs themselves can disrupt differentiation of OL precursor cells in vitro and remyelination in vivo 16-18. An independent effect of ARV drugs on WM pathology is clinically important not only in the care of HIV+ adolescents, but also in uninfected adolescents who use pre-exposure prophylaxis (PrEP), a combination of two nucleoside reverse transcriptase inhibitors, emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), to prevent HIV infection. Our preliminary data indicate that several ARV drugs, including FTC and TDF, inhibit the progression of OL maturation in vitro through lysosomal dysfunction suggesting a role for organellar stress. Thus, we hypothesize that HIV, ART and PrEP disrupt developmental myelination via organellar stress contributing to the multifaceted CNS deficits observed in adolescents and young adults. We propose to: 1) Determine the mechanisms by which HIV- induced neuroinflammation disrupts OL maturation in adolescents, 2) Determine the role of lysosome dysfunction in ART-induced changes in OL maturation in rodent models of adolescence and young adulthood, and 3) Compare OL maturation and myelination measures in Aims 1 and 2 to magnetic resonance imaging measures of WM volume and integrity in adolescent rats and a pre-existing cohort of adolescent humans.