The overriding goal of R01DA013324 is to investigate the host genetic basis for spontaneous clearance of hepatitis C virus (HCV) infection in persons with and without HIV. After infection, HCV either replicates for decades at high levels or is spontaneously cleared. This discrete outcome is of paramount public health importance because persons who have persistent infection (but not those who clear) have a markedly increased risk of liver failure or cancer, and in 2007 in the US, HCV surpassed HIV as a cause of death. There is overwhelming evidence that host genetic differences explain why some persons clear infection and others have viral persistence. The two outcomes occurred even when persons were accidently infected with the same viral inoculum, and persons of African descent are 5 times less likely to clear than Caucasians. To investigate the genetic basis for HCV clearance, we compare DNA sequences of persons with HCV antibodies but not HCV RNA (clearance) to those with both antibodies and RNA (persistence). Because of shared transmission routes HIV/HCV coinfection is common, and our studies also focus on HIV allowing comparisons of mechanisms of control of two leading chronic viral infections. Similarities and differences in the genetic determinants of control inform efforts to combat each viral infection and may also shed insights into post-viral inflammatory syndromes. We, and our collaborators, have already made multiple important discoveries that have major implications with HCV and possibly HIV vaccine development and disease control. However, important questions remain and can now be answered due to technological advances in genetic testing and the infrastructure of our HCV clearance research consortium.

Public Health Relevance

Understanding the genetic basis for control of hepatitis C virus (HCV) and HIV infections contributes to disease control by informing vaccine development. Related findings also may have broad implications as discovery of novel genes and novel diseases mechanisms also inform research into other infectious diseases and discovery of pathways of persistent immune activation might shed light on the growing challenge of post-viral inflammatory syndromes.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01DA013324-16A1
Application #
8789985
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Khalsa, Jagjitsingh H
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
None
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Seaberg, E C; Witt, M D; Jacobson, L P et al. (2014) Differences in hepatitis C virus prevalence and clearance by mode of acquisition among men who have sex with men. J Viral Hepat 21:696-705
Zignego, A L; Wojcik, G L; Cacoub, P et al. (2014) Genome-wide association study of hepatitis C virus- and cryoglobulin-related vasculitis. Genes Immun 15:500-5
Chattergoon, Michael A; Latanich, Rachel; Quinn, Jeffrey et al. (2014) HIV and HCV activate the inflammasome in monocytes and macrophages via endosomal Toll-like receptors without induction of type 1 interferon. PLoS Pathog 10:e1004082
Osburn, William O; Snider, Anna E; Wells, Brittany L et al. (2014) Clearance of hepatitis C infection is associated with the early appearance of broad neutralizing antibody responses. Hepatology 59:2140-51
Wojcik, Genevieve; Latanich, Rachel; Mosbruger, Tim et al. (2014) Variants in HAVCR1 gene region contribute to hepatitis C persistence in African Americans. J Infect Dis 209:355-9
Prokunina-Olsson, Ludmila; Muchmore, Brian; Tang, Wei et al. (2013) A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet 45:164-71
Thomas, David L (2013) Global control of hepatitis C: where challenge meets opportunity. Nat Med 19:850-8
Duggal, Priya; Thio, Chloe L; Wojcik, Genevieve L et al. (2013) Genome-wide association study of spontaneous resolution of hepatitis C virus infection: data from multiple cohorts. Ann Intern Med 158:235-45
Liu, Lin; Fisher, Brian E; Thomas, David L et al. (2012) Spontaneous clearance of primary acute hepatitis C virus infection correlated with high initial viral RNA level and rapid HVR1 evolution. Hepatology 55:1684-91
Salgado, Maria; Kirk, Gregory D; Cox, Andrea et al. (2011) Protective interleukin-28B genotype affects hepatitis C virus clearance, but does not contribute to HIV-1 control in a cohort of African-American elite controllers/suppressors. AIDS 25:385-7

Showing the most recent 10 out of 38 publications