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HIV/HCV Co-infection
Progression to End Stage
Liver Disease
1
Aileen Patterson
HIV/HCV Co-infection
• Introduction to HCV
• Introduction to HIV
• Co-infection
• General effects
• Specific mechanisms
• Treatment
Hepatitis C Virus (HCV)
• 3% of the world population infected
• >200 000 in Canada
• Blood is primary mode of transmission
• High degree of chronicity ( 50-85%)
• Causes liver cirrhosis, steatosis, and HCC
• Treatment efficacy <50%
• No vaccine
James A. Perkins http://www.the-
scientist.com
HCV Life Cycle
Lindenbach and Rice 2005
Genome Organization
Moradpour et al 2007.
Models to Study HCV
• HepG2, Huh7 cells, primary hepatocytes,
chimpanzee
• Replicon system, JFH-1
http://www.nature.com/nrd/journal/v1/n11/images/nrd942-f1.gif
Liver Disease Progression
Human Immunodeficiency Virus (HIV)
• >40 million people infected worldwide
• Bloodborne pathogen
• Infects immune cells and weakens immune system
• Progresses to AIDS
• Treated with HAART
HIV Genome
http://student.ccbcmd.edu/courses/bio141/lecguide/unit3/viruses/hivgenes.html
HIV/HCV Co-infection
• Shared routes of transmission
• 30-40% HIV patients are co-infected with
HCV
• Liver failure emerging as leading cause
of mortality
General Effects
• Immune regulation by HIV
• Increase in HCV RNA levels
• Faster progression to end stage liver
disease
Immune Regulation by HIV
• CD8+ and CD4+ T cell response required for
HCV clearance
• HIV attacks these cells
• Leads to chronic HCV
infection
http://hepatmon.com/view/?id=180
Increased HCV RNA
• HIV usually treated with HAART
• Leads to increase in HCV RNA
• Possible explanations:
• Lysis of HCV-infected cells releases HCV
particles
• Reduced competition for entry into cells
• Reduced IFN induced by HIV
Increased Steatosis and Fibrosis
• Co-infection leads to a faster progression rate to
fibrosis at almost all stages of steatosis
Gaslightwala and Bini. 2006
Faster Progression to Liver Disease
HIV/HCV HCV
Co-infection Monoinfection
Liver Cirrhosis 6.9 years 23.2 years
Hepatocellular 17.8 years 28.1 years
Carcinoma
Mechanisms of Disease Progression
• HIV can infect hepatic stellate cells
(HSCs)
• Hepatocyte apoptosis
• HIV upregulates HCV replication
Activated HSC Leads to Fibrogenesis
Collagen 1
MCP-1
www.medscape.com
17
Tuyama et al 2010
HIV Infects HSCs
• HSCs express CCR5 and
CXCR4
• HIV can infect activated HSCs
• promotes expression of
collagen 1
• promotes secretion of MCP-1
• HSC can transfer HIV to
lymphocytes through cell-cell
contact
Tuyama et al 2010
18
Hepatocyte Apoptosis
• HIV gp120 and HCV E2 induce apoptosis in HepG2 cells
Munshi et al 2003
Munshi et al 2003
• Neutralizing antibody (12G5) against co-receptor partially
blocks apoptosis
Hepatocyte Apoptosis
• HIV and HCV envelope
proteins lead to AKT
dephosphorylation
• AKT is a key regulator in
cellular survival pathway
• Apoptosis of hepatocytes
may contribute to disease
Munshi et al 2003
progression
HIV Increases HCV Replication
• OR6 cells have a bicistronic HCV replicon encoding Renilla
luciferase that measures HCV replication
World J Gastroenterol. 2010 16(2): 184-192
• HIV envelope protein gp120 increase HCV replication
Lin et al 2008
TGF-β1 Expression Upregulated by HIV
Infection
A
• HIV increases TGF-β1
expression
• TGF-β1 shown to B
enhance HCV replication
in dose dependent
manner
Lin et al 2008
HAART
• Current treatment for HIV infected individuals
is a combination of antiviral compounds:
•Nucleoside reverse transcriptase inhibitors
•Non-nucleoside reverse transcriptase inhibitors
•Protease inhibitors
• Decreases HIV RNA levels and increases
CD4+ count
• Risk of hepatotoxicity
Treatment
• Combined HCV and HIV therapies not normally
administered together to prevent hepatotoxicity
• Liver transplant
• Immunosuppressive drugs
• Drug interactions
Summary
• HCV infection leads to liver steatosis, fibrosis, cirrhosis and hepatocellular
carcinoma.
• HIV targets CD4+ cells and leads to destruction of the host immune system.
• HIV/HCV co-infection has a negative impact on HCV infection, by worsening liver
damage and increasing progression to end stage liver disease.
• HIV is able to infect activated HSCs, thereby inducing profibrotic and
proinflammatory resonses by increasing expression of type I collagen and MCP-1,
respectively.
• HCV E2 and HIV gp120 envelope proteins co-operatively induce hepatocyte
apoptosis through dephosphorylation of AKT.
• HIV gp120 enhances HCV replication through TGF-β1 induction.
• HAART therapy for HIV and interferon therapy for HCV may cause chronic
hepatotoxicity, so careful monitoring is required.
Key References
Blackard JT and KE Sherman. 2008. HCV/HIV co-infection: time to re-evaluate the role of HIV in the liver? J
Viral Hep. 15: 323-330.
Gaslightwala, I., and E. J. Bini. 2006. Impact of human immunodeficiency virus infection on the prevalence and
severity of steatosis in patients with chronic hepatitis C virus infection. J. Hepatol. 44:1026-1032.
Lin W, Weinberg EM, Tai AW, Peng LF, Brockman MA, Kim KA, Kim SS, Borges CB, Shao RX and RT Chung.
2008. HIV increases HCV replication in a TGF-β-dependent manner. Gastroenterology. 134: 803-811.
Moradpour D, Penin F, and CM Rice. 2007. Replication of hepatitis C virus. Nature Reviews. 5:453-463.
Munshi N, Balasurbramanian A, Koziel M, Ganju RK, and JE Groopman. 2003. Hepatitis C and human
immunodeficiency virus envelope proteins cooperatively induce hepatocytic apoptosis via an innocent
bystander mechanism. J Infect. Dis. 188: 1192-1204.
Petrovic LM. 2007. HIV/HCV co-infection:histopathological findings, natural history, fibrosis, and impact of
antiretroviral threatment: a review article. Liver Internat. 598-606.
Tuyami AC, Hong F, Saiman Y, Wang C, Ozkok D, Mosoian A, Chen P, Chen BK, Klotman ME, and MB Bansal.
2010. human immunodeficiency virus (HIV)-1 infects human hepatic stellate cells and promotes collagen I and
monocyte chemoattractant protein-1 expression: implications for the pathogenesis of HIV/hepatitis C virus-
induced liver fibrosis. Hepatol. 52: 612-622.
