Dataset Information

Genetic Determinants of Viral Clearance in HCV-Infected Populations

ABSTRACT:

The World Health Organization estimates there are 170 million persons with HCV infection worldwide, and an estimated 4 million persons are infected in the United States. Persistent HCV infection can cause cirrhosis and hepatocellular cancer. Long term disease consequences do not occur in persons who spontaneously recover. It is not known why 10-40% recover from hepatitis C (and are not at increased risk of cirrhosis and cancer), but that knowledge would contribute to efforts to treat and/or prevent HCV infection. The overall purpose of this study is to investigate the host genetic basis for recovery from hepatitis C virus (HCV) infection. There is strong evidence that host genetic differences determine HCV recovery. After accidental exposure to the same HCV inoculum, some persons recover while others develop persistent infection. Recovery from HCV infection is an outstanding phenotype for genetic studies since both viral exposure and viral recovery can be ascertained with high sensitivity and specificity and since there are no known viral or environmental determinants.

The study group is comprised of an ethnically and geographically diverse international population. All cohorts comprising this study group of 3350 individuals are well characterized. This case-control study is comprised of approximately 40% clearance individuals who are matched by age and HIV status within their respective cohorts at a ratio of 1:1 or 1:2 with HCV chronically infected individuals.

PROVIDER: phs000248 | dbGaP |

SECONDARY ACCESSION(S): PRJNA75649PRJNA75651

REPOSITORIES: dbGaP

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			Action	DRS
	GapExchange_phs000248.v1.p1.xml	Xml
	dbGaPEx2.1.5.xsd	Other
	Study_Report.phs000248.CIDR_HCV.v1.p1.MULTI.pdf	Pdf
	manifest_phs000248.CIDR_HCV.v1.p1.c1.GRU-IRB.pdf	Pdf
	datadict_v2.xsl	Other

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Project description:Hepatitis A virus (HAV) is a hepatotropic human picornavirus that has been associated only with acute infection. Its pathogenesis is not well understood since there have been few recent studies in animal models using modern methodologies. We characterized HAV infections in three chimpanzees, quantifying viral RNA by qRT-PCR and examining critical aspects of the innate immune response including intrahepatic interferon-stimulated gene expression. We compared these infection profiles with similar studies of chimpanzees infected with hepatitis C virus (HCV), a hepatotropic flavivirus that frequently causes persistent infection. Surprisingly, HAV-infected animals exhibited very limited induction of type I interferon-stimulated genes in the liver compared to chimpanzees with acute resolving HCV infection, despite similar levels of viremia and 100-fold greater quantities of viral RNA in the liver. Minimal ISG15 and IFIT1 responses peaked 1-2 weeks after HAV challenge, then subsided despite continuing high hepatic viral loads. An acute inflammatory response at 3-4 weeks correlated with the appearance of virus-specific antibodies, and both apoptosis and proliferation of hepatocytes. Despite this, HAV RNA persisted in the liver for months, remaining present long after its clearance from serum and feces and revealing dramatic differences in the kinetics of clearance in the three compartments. Viral RNA was detected in the liver for significantly longer (35 to >48 weeks) than HCV RNA in animals with acute resolving HCV infection (10-20 weeks). Collectively, these findings suggest that early HAV infection is far stealthier than HCV infection and represents a distinctly different paradigm in viral-host interactions within the liver. Chimpanzee liver was biopsied during an acute HAV infection. Chimp 1 and 2 had two baseline samples. Chimp 3 used the baselines from chimps 1 and 2. Chimp 1 had 8 samples during the HAV acute infection. Chimp 2 had 9 samples during the HAV acute infection. Chimp 3 had 4 samples during the HAV acute infection.

Project description:Chronic viral hepatitis after infection with hepatotropic viruses like hepatitis B virus (HBV) affects 300 million persons worldwide, which as the result of chronic immune-mediated hepatic inflammation cause liver cirrhosis and cancer being responsible for 800.000 deaths per year3. Chronic viral hepatitis is maintained by failure of the host´s immune response to control viral infection, but the mechanisms for this inability of virus-specific CD8 T cells to eliminate HBV-infected hepatocytes remain unclear. Here, we demonstrate that during persistent experimental infection with hepatotropic viruses and HBV replication in hepatocytes all virus-specific CD8 T cells present in the liver expressed the tissue-residency markers CXCR6 and CD69. However, RNAseq analysis revealed that CXCR6+CD8 T cells during persistent hepatotropic infection were retained in the liver because of antigen-recognition rather than a transcriptional tissue-residency program, in contrast to canonical liver-resident memory CXCR6+CD8 T cells emerging after resolved infection. Whereas during persistent infection with a model virus like lymphocytic choriomeningitis virus with broad tissue and cell tropism exhausted CD8 T cells show graded loss of effector functions, hepatic virus-specific CXCR6+CD8 T cells during persistent infection with hepatotropic viruses were blinded and completely non-responsive to stimulation in absence of a canonical tox exhaustion signature. Rather, in blinded liver CXCR6+CD8 T cells, transcription factor network analysis revealed Crem, the cAMP-responsive-element-modulator, as the only transcription factor discreetly active in CD8 T cells with complete loss of effector function during persistent hepatotropic infection. Similarly, single cell RNA-sequencing of peripheral blood HBcore-specific CD8 T cells from chronic hepatitis B patients also revealed enhanced CREM activity. Notably, knock-out of the inhibitory CREM/ICER gene in T cells failed to rescue protective T cell immunity during persistent infection with hepatotropic viruses pointing towards post-translational mechanisms relevant for enhanced Crem activity and loss of effector function. Indeed, T cell receptor-associated signalling was blocked in blinded antigen-specific CXCR6+CD8 T cells, that in situ during persistent hepatotropic infection were in close proximity to liver sinusoidal endothelial cells producing high amounts of cAMP-inducing prostanoids. Inhibitory cAMP/PKA/CSK activity increased CREM activity and disconnected CXCR6+CD8 T cells from activation signalling through the T cell receptor. Thus, enhanced CREM expression identifies blinded liver CXCR6+CD8 T cells, but loss of effector functions is caused by post-translational prevention of signalling, which identifies novel molecular targets for immune monitoring and immune therapy of chronic hepatitis B.

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Genetic Determinants of Viral Clearance in HCV-Infected Populations

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