Study Elucidates a Mechanism for HCV Evasion of Immune Response
Johns Hopkins University School of Medicine researchers provide insight on how HCV evades the human immune response and why developing an HCV vaccine has been difficult.
The World Health Organization (WHO) reports that approximately 150 million individuals worldwide are afflicted with a chronic hepatitis C viral (HCV) infection. Although HCV can cause acute infections that are spontaneously cleared within a short time period, chronically infected individuals are at serious risk of developing liver-related disease. The WHO estimates that around 700,000 individuals die every year due to complications arising from HCV-related infection. With the new direct acting antiviral (DAA) therapy, the HCV treatment landscape is sure to change, with a potential decrease in the mortality and morbidity associated with HCV infections. Nonetheless, there is a dire need for a prophylactic measure in the form of an HCV vaccine, which has proven elusive thus far.
A group based at the Johns Hopkins University School of Medicine, led by principal investigator Dr. Justin Bailey, MD, PhD, has published an article in PLOS Pathogens that provides insight on how HCV evades the human immune response and why developing an HCV vaccine has been difficult. Per the authors, to develop a successful vaccine against a virus that is as genetically diverse as HCV, the vaccine must be able to elicit an immune response that targets a large range of viral forms.
The authors generated a library of E1 and E2 genes, which code for viral envelope glycoproteins, to examine the link between sequence and sensitivity to two powerful, broadly neutralizing antibodies (bNAbs), HC33.4 and AR4A. The library consisted of naturally occurring HCV E1E2 genes, of which 113 produced viable HCV pseudoparticles (HCVpp) which were used for further study. The authors utilized the library to first examine any variations in the HCVpp library in the binding region of the two bNAbs examined. Results showed that the HC33.4 antibody show some variability at one position examined while the AR4A antibody showed no variability in the epitopes examined.
Dr. Bailey and his colleagues then measured if the HCVpp library can mediate successful cell entry when incubated with either of the two bNAbs. Results showed that HC33.4 neutralized 88% of the HCVpp library while AR4A neutralized 85.8%. The authors were surprised to find large variability in each bNAb’s ability to neutralize the HCVpp library. In a press release, Ramy El-Diwany, lead investigator on the study, is quoted saying, “We discovered that there was a lot of naturally occurring resistance, meaning we may need to greatly expand the set of viruses we use to evaluate potential vaccines.”
The authors of the study then utilized two computational modeling approaches to determine which E1E2 sequences are associated with HCVpp resistance to HC33.4 and AR4A. It was determined that changes at amino acid positions 242, 403, and 438 are important for determining sensitivity of HCV to bNAbs. To test the modeling predictions, the authors generated mutants using a site-directed mutagenesis approach and then tested these mutants for sensitivity to HC33.4 and AR4A, revealing that two polymorphisms, at positions 403 and 438, are modulators of resistance to both bNAbs.
To elucidate the mechanism by which these HCV variants modulate resistance to neutralizing antibodies, the authors examined binding of wild type and mutant HCV variants to scavenger receptor class B type I (SR-BI), which is a receptor known to play an important role in HCV entry into the cell. They determined that these two polymorphisms change binding to SR-B1, thereby demonstrating a new mechanism that HCV uses to evade the immune response.
Highlighting the importance of this work in illuminating how HCV manages to dodge the immune system, Dr. Bailey is quoted in the press release, “These are the mutations we believe may allow the viruses to avoid being blocked by antibodies altogether. If you think of it like a race, the antibody is trying to bind to the virus before it can enter the cell. We think this mutation may allow the virus to get into the cell before it even encounters the immune system.”
Samar Mahmoud graduated from Drew University in 2011 with a BA in biochemistry and molecular biology. After two years of working in industry as a quality control technician for a blood bank, she went back to school and graduated from Montclair State University in 2016 with a MS in pharmaceutical biochemistry. She is currently pursuing her PhD in molecular and cellular biology at the University of Massachusetts at Amherst.