Understanding white matter deficits in HIV positive children and adolescents

Students

Faculty

Professor of Pathology

Project Summary

This summer I worked with Dr. Kelly Jordan-Sciutto and Dr. Judy Grinspan in the University of Pennsylvania Dental School and the Neurology Department in the Children’s Hospital of Philadelphia.  Our research primarily focused on oligodendrocytes, the myelin-producing glia cells in the central nervous system and how they are affected in the presence of HIV infection and antiretroviral therapies (ART). Approximately 30-50% of HIV+ patients develop HIV-associated neurocognitive disorders (HAND), which is a spectrum of cognitive, motor and behavioral impairments. Since the development of ART to control HIV replication, the most severe form of HAND has decreased; however, less severe forms of HAND still occur in roughly 50% of HIV+ patients. 
 
Previous studies from our lab have shown that some antiretroviral drugs inhibit the differentiation of oligodendrocytes, the myelin-producing support cells in the brain, and could be contributing to the neurocognitive deficits seen in HAND (Jensen et al, 2015). I tested a front-line ART drug from the integrase strand transfer inhibitors (INSTIs): bictegravir. We hypothesized that bictegravir would alter oligodendrocyte differentiation. To determine the direct effect on oligodendrocytes, oligodendrocyte progenitor cells (OPCs) were isolated from brain of postnatal rats and cultured. The OPCs were placed in medium to induce differentiation and at the same time, treated with three different concentrations of each ART drug for 72 hours. After treatment, the cells were labeled with antibodies to immature marker GalC, mature marker PLP, and nuclear label DAPI. The slides were imaged and the cells counted. Cells treated with the highest dose of bictegravir showed significantly lower numbers of GalC(+) and PLP(+) cells compared to the DMSO control, while the cells treated with the medium and low dose had no significant change in differentiation. Exploration of the effects of these drugs will provide insights into the effect of ART on HAND pathologies and the role of oligodendrocyte differentiation in HIV(+) individuals. 
 
I came into the Grinspan lab knowing more about HIV than I did about the brain and had very little knowledge about oligodendrocytes. Through my research experience this summer, I have gained so much comprehension and appreciation for these cells. I also learned many useful techniques such as cell culture and immunocytochemistry, as well as statistical analysis and experimental design. Developing relationships with the other researchers in the lab exposed me to a lot of different kinds of projects and techniques. I found the research so interesting and the researchers so welcoming that I have decided to continue this research during the school year.