Increasing evidence supports a central role for the innate immune system in the host's response against viral infections. In particular, natural killer (NK) cells represent a critical eariy cytolytic effector cell subset that are able to spontaneously lyse virally infected cells without the need for prior anfigen sensitizafion. In the context of HCV infecfion, a small number of studies have focused on this cell subset as these cells have been implicated in the eariy control of a number of viral infecfions, these cells are abundant within the liver, and that in addition to the direct antiviral effects of interferon(IFN)-a (used to treat the infection), IFN-a directly acfivates the antiviral capacity of NK cells. Furthermore, compelling epidemiologic evidence has identified a strong association between homozygosity of NK killer immunoglobulin-like receptor gene {KIR2DL3) and its ligand HLA-C alleles in the Cl family, suggesting that NK cells may truly play a central role in this antiviral protection. However the direct role of NK cells in HCV clearance still remains to be determined. Accumulating evidence suggests that chronic HCV infection is associated with the accumulafion of a phenotyplcally and potentially functionally altered NK cells. However, HCV resolution occurs within the first weeks to months of HCV infection in 15-30% of infected individuals. This eariy control occurs at a fime when the adaptive immune response is just being induced. Thus several groups have speculated that innate, including NK cells, rather than adaptive immune responses may play a major role in eariy containment. Thus in this proposal we aim to define the role of NK cells in acute HCV infecfion and to determine the NK cell immunolpgical signatures associated with the ability to clear HCV infecfion. Thus we propose to first carefully phenotyplcally, transcriptionally, and functionally characterize NK cells in acute HCV infection among individuals that resolve compared to those that become chronically infected;to then dissect the role of the protecfive KIR2DL3/HLA-C1 combined genotype on NK cell clonal expansions and antiviral funcfion;and finally to investigate how IFN-a and other IFNs may contribute to the specific expansion and funcfional activafion of protective NK cell populations with unique antiviral properties. Elucidafing the role of NK cells in the resolution of HCV infection may provide potentially novel opportunifies to enhance the activity of particular NK cell populafions to gain greater control over the virus and enhance HCV clearance rates.

Public Health Relevance

In a subset of patients, HCV resolution occurs within the first weeks/months of infecfion, at a fime when the adapfive immune response is just developing. The strong association of HCV clearance with particular Natural Killer (NK) cell receptor/ligand genotypes and the abundance of NK cells within the liver support a central role for NK cells in the resolufion of HCV infection. Thus, we propose to determine the role of NK cells in acute HCV infection, providing new potenfial therapeufic avenues to enhance the activity of particular NK cell populafions to drive HCV clearance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI066345-08
Application #
8382261
Study Section
Special Emphasis Panel (ZAI1-BP-M)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
8
Fiscal Year
2012
Total Cost
$192,707
Indirect Cost
$80,491
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Torres-Cornejo, Almudena; Lauer, Georg M (2017) Hurdles to the Development of Effective HBV Immunotherapies and HCV Vaccines. Pathog Immun 2:102-125
Wolski, David; Foote, Peter K; Chen, Diana Y et al. (2017) Early Transcriptional Divergence Marks Virus-Specific Primary Human CD8+ T Cells in Chronic versus Acute Infection. Immunity 47:648-663.e8
Rodrigo, Chaturaka; Walker, Melanie R; Leung, Preston et al. (2017) Limited naturally occurring escape in broadly neutralizing antibody epitopes in hepatitis C glycoprotein E2 and constrained sequence usage in acute infection. Infect Genet Evol 49:88-96
Rodrigo, C; Eltahla, A A; Bull, R A et al. (2017) Phylogenetic analysis of full-length, early infection, hepatitis C virus genomes among people with intravenous drug use: the InC3 Study. J Viral Hepat 24:43-52
Vergara, C; Thio, C; Latanich, R et al. (2017) Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections. Genes Immun 18:82-87
Rodrigo, Chaturaka; Eltahla, Auda A; Bull, Rowena A et al. (2016) Historical Trends in the Hepatitis C Virus Epidemics in North America and Australia. J Infect Dis 214:1383-1389
Page, Kimberly; Mirzazadeh, Ali; Rice, Thomas M et al. (2016) Interferon Lambda 4 Genotype Is Associated With Jaundice and Elevated Aminotransferase Levels During Acute Hepatitis C Virus Infection: Findings From the InC3 Collaborative. Open Forum Infect Dis 3:ofw024
Gunn, Bronwyn; Schneider, Jeffrey; Shansab, Maryam et al. (2016) Enhanced binding of antibodies generated during chronic HIV infection to mucus component MUC16. Mucosal Immunol 9:1549-1558
Doyle, J S; Deterding, K; Grebely, J et al. (2015) Response to treatment following recently acquired hepatitis C virus infection in a multicentre collaborative cohort. J Viral Hepat 22:1020-32
Sacks-Davis, Rachel; Grebely, Jason; Dore, Gregory J et al. (2015) Hepatitis C Virus Reinfection and Spontaneous Clearance of Reinfection--the InC3 Study. J Infect Dis 212:1407-19

Showing the most recent 10 out of 55 publications