Long Caela C, Festa Lindsay K, Cruz-Berrios Melanie, Johnson Teshawn D, Mitchell Claire H, Jordan-Sciutto Kelly L, Grinspan Judith B
Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Glia. 2025 Oct;73(10):1967-1988. doi: 10.1002/glia.70050. Epub 2025 Jul 17.
A disproportionate percentage of adolescents are diagnosed with human immunodeficiency virus (HIV) in the United States each year. Preexposure prophylaxis (PrEP), an antiretroviral regimen, is effective at preventing the transmission of HIV to adolescents at substantial risk for acquiring HIV. However, other select antiretrovirals have been shown to cause white matter deficits in experimental models. Adolescents taking PrEP are uniquely vulnerable to myelin impairments as the adolescent brain undergoes high rates of myelination. Here, we report that PrEP significantly reduced oligodendrocyte maturation in adolescent rats. Furthermore, cultures of primary rat oligodendrocyte progenitors treated with PrEP showed inhibited oligodendrocyte differentiation through deacidification of lysosomes resulting in lysosomal accumulation of myelin proteins. Acidic nanoparticle co-administration with PrEP prevented PrEP-induced oligodendrocyte maturation impairments both in vivo and in vitro. These studies suggest uninfected adolescents are vulnerable to PrEP-induced oligodendrocyte impairments and identify maintenance of lysosome pH as a critical factor in antiretroviral design.
在美国，每年被诊断出感染人类免疫缺陷病毒（HIV）的青少年比例过高。暴露前预防（PrEP）是一种抗逆转录病毒疗法，对于预防HIV传播给有很大感染风险的青少年有效。然而，其他特定的抗逆转录病毒药物在实验模型中已被证明会导致白质缺陷。由于青少年大脑正经历高速髓鞘形成过程，服用PrEP的青少年特别容易出现髓鞘损伤。在此，我们报告PrEP显著降低了青春期大鼠少突胶质细胞的成熟。此外，用PrEP处理的原代大鼠少突胶质前体细胞培养物显示，通过溶酶体去酸化抑制少突胶质细胞分化，导致髓鞘蛋白在溶酶体中积累。酸性纳米颗粒与PrEP共同给药可在体内和体外预防PrEP诱导的少突胶质细胞成熟障碍。这些研究表明，未感染的青少年易受PrEP诱导的少突胶质细胞损伤影响，并确定溶酶体pH的维持是抗逆转录病毒药物设计中的关键因素。
