Examination of SHIV Tropism Dependence on Co-receptor CCR5 after PrEP with MVC Failed in Macaques (2014)
Undergraduates: Blake Hauser, Maria Bednar, Li-Hua Ping, Ronald Swanstrom
Faculty Advisor: Ronald Swanstrom
Department: Biology
Approximately 6,300 new HIV-1 infections occur daily. HIV-1 entry into host cells depends on the Env protein¿s use of both the CD4 receptor and one of two co-receptors, CCR5 or CXCR4, with the majority using CCR5. Maraviroc (MVC) serves as a potent antagonist of the CCR5 co-receptor. Due to evidence that transmitted viruses use CCR5, Dr. Garcia-Lerma¿s lab at the CDC used a macaque model to investigate efficacy of MVC as a pre-exposure prophylaxis (PrEP) drug. After receiving oral MVC, macaques were challenged with a SHIV (a combination of Simian Immunodeficiency Virus and HIV-1) infection to evaluate the efficacy of MVC in preventing rectal transmission. The trial failed, with 5/6 test subjects becoming infected along with 3/4 controls. We are evaluating the source of this failure.
We received samples from 7 of the trial monkeys and of the infecting SHIV, SHIV162P3. Phylogenic trees and highlighter plots were generated from single genome sequencing to represent genetic diversity, which proved low. The env gene from nineteen amplicons has been cloned as a representative sample. Infectivity of affinofile cells with variable CCR5 expression levels will be evaluated in the presence and absence of MVC to determine if high CCR5 expression levels allowed SHIV infection despite MVC¿s presence.
Work is ongoing, and results are expected within the month. Conclusions will then be drawn regarding the role of CCR5 expression levels in determining MVC¿s efficacy as HIV-1 PrEP drug.