UNIVERSITY OF MANITOBA, MEDICAL MICROBIOLOGY

HIV and HCV interactions in end-stage liver disease

How things can always be worse...
Jonathan Audet 12/7/2011

Key points:
Hepatitis C virus (HCV) affects about 30% of HIV patients and as high as 90% of HIV positive IV drug users. It also dramatically reduces life expectancy. HIV can kill and/or sensitize hepatic cells resulting in liver injury. The damages caused to the immune system allow increased replication of HCV and thus, increased damage. The depletion of Th17 cells in the gut might be an important factor in accelerating liver fibrosis, as hepatic stellate cells are stimulate by the microbial products that leak through the gut and secrete profibrotic cytokines and collagen type I. HAART agents have become less hepatotoxic and are therefore of great help in the management of HIV in coinfection patients.

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HIV & HCV in end-stage liver disease

Introduction
As of their 2011 Global HIV/AIDS Response Progress Report, the World Health Organization (WHO) estimates the number of people living with HIV to be approximately 34 million worldwide. (1) Despite modern therapies, which increase the lifespan of those who are infected, there are no treatments and no vaccines currently licensed for HIV. The main route of transmission is through sexual intercourse, although tainted blood (such as on needles used by drug users or blood used for transfusions) can also transmit the virus. It is currently estimated that 20-30% of HIV patients are also infected with Hepatitis C Virus (HCV), this fraction can go up to 90% among IV drug users. The main route of transmission of HCV is through contaminated blood, usually from re-use of syringes or from blood transfusions. It can also be transmitted through sexual intercourse, albeit less frequently. The shared routes of transmission mean that high-risk behavior for one virus also predisposes to being infected by the other. Those patients coinfected with HIV and HCV usually have a dramatically reduced life expectancy due to the acceleration of liver damage. For example, those infected with HCV alone will be chronically infected for about 23.2 years at the onset of cirrhosis, whereas in those coinfected with both HIV and HCV the onset of cirrhosis happens around 6.9 years after HCV infection. (2) The present summary will, first, present some background information about liver physiology, the immune system and viral pathogenesis; then discuss how these three aspects interact to aggravate and accelerate the progression to end-stage liver disease (ESLD).

Background
Physiology Kupffer cells are macrophages found in the livers blood vessels, they are specialized for the removal of erythrocytes and complement covered microbes (Figure 1). They also possess the TLR4 receptor, allowing them to sense LPS. Upon LPS stimulation, Kupffer cells will secrete reactive oxygen species (ROS) and tumor necrosis factor (TNF) (3) which will stimulate hepatic stellate cells (HSC). (4) The HSCs will then upregulate TLR4/CD14/MD2 and also start producing profibrotic cytokines and collagen type I. (4) Immunology: The Th17 response Of the 6 currently known T helper differentiation paths, the Th1 and Th2 are the most studied. In the case of HIV enhanced liver disease however the Th17 response is suspected to be quite important.

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HIV & HCV in end-stage liver disease

The Th17 response is mainly responsible for mucosal extracellular pathogen monitoring and response. Th17 cells are enriched in the lungs and the gastro-intestinal tract. The hallmark of these cells is the production of IL-17 and IL-22. There have been reports that IL-17 induces the formation of tight junctions in intestinal epithelial cells (5).

Human Immunodeficiency Virus Infection with HIV normally starts with the infection of macrophages or dendritic cells at mucosal surfaces. The virus will then be transmitted to CD4+ lymphocytes and spread mainly in that cell population. There have been reports of HIV causing direct death of hepatocytes through CXCR4 signalling by gp120 (6) and indirectly by increasing TRAIL sensitivity in hepatocytes (7) . Also HIV increases CD4+ T cell death by increasing both Fas and sFasL expression (8).
HIV produces an initial acute infection that gets rapidly controlled by the immune system and transforms into a chronic infection inducing a high turn-over of CD4+ T cells.

Hepatitis C Virus HCV is a positive single-stranded RNA virus of the family Flaviviridae. It causes a hepatitis that can be acute and cleared by the immune system (10-60% of cases (9)) or go on to become a chronic infection. One of the strategies for the virus to escape clearance is to possess a high mutation rate. Similar to HIV, HCV needs to copy its genome, although it makes a negative sense RNA copy and not a DNA copy, and this step in viral replication is very error- prone. This allows the virus to generate quasispecies and means that most people infected with HCV can carry viruses that are quite different from one another. (10)
The currently accepted treatment for HCV infection is pegylated interferon and ribavirin (11), although there are two new drugs approved in 2011 by the FDA. HCV has been shown to increase Fas expression on CD4+ T cells but not soluble FasL (sFasL) which leads to increased sensitivity to Fas-mediated apoptosis of CD4+, but the virus itself does not produce the increased apoptosis. (8) There have also been reports of HCV infecting non-hepatic cells, including T and B cells. (12) An untreated, or unresponsive, hepatitis C infection will usually result in a cirrhotic liver that can develop hepatocellular carcinomas. In cirrhosis, the parenchymal tissue in the liver, i.e. the actual hepatocytes, will be slowly replaced with scar tissue and collagen leading to a loss of function of the liver. The only treatment for a cirrhotic liver is transplantation.

Proposed interactions
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HIV & HCV in end-stage liver disease

There are two ways HIV can aggravate the damage caused by HCV: 1) indirectly, by damaging the immune system, HIV can allow HCV to cause more damage to the liver; and, 2) directly, by sensitizing the liver cells or otherwise increasing hepatocyte death.

Indirect: How immune system pathologies contribute to liver disease Because both viruses increase the expression of Fas on CD4+ T cells, these become highly sensitized to the action of sFasL and will be depleted quite efficiently by the increased that HIV provokes. (8) Here, these viruses act synergistically to deplete the CD4 population. Because CD4+ T cells are orchestrators of the immune response, the efficiency of the anti-HCV response is diminished and more liver damage can result.
The persistence of the antigens will also bring CD8+ T cell exhaustion which will reduce the effectiveness of the immune response to both viruses, but mainly allows for increased HCV RNA levels in the blood, indicating more replication is probably happening in the liver. Because Th17 cells are a subset of CD4+ T cells, they can and are infected by HIV. This is especially true in the gut epithelium. In a normal individual, when the tight junctions between the enterocytes start to loosen, microbial products such as LPS and DNA cross into the tissue (microbial translocation) and blood and stimulate the immune cells that reside in the gut. Upon stimulation Th17 cells will secrete large amounts of IL-17. This cytokine tends to stimulate the formation of tight junctions and restores the integrity of the epithelium. (4,13) In contrast, during HIV infection, Th17 cells are effectively depleted in the intestinal mucosa, leading to loss of integrity and increased microbial translocation. This increase in microbial products stimulates Kupffer cells and HSCs, the latter increase the rate at which they produce profibrotic cytokines and deposit collage type I. (4) This hypothesis, however, has yet to be clearly demonstrated. (Figure 2)

Direct: Possible interactions between the viruses

It has recently been shown that HIV can increase the sensitivity of hepatic cell lines to TRAIL-induced apoptosis or even cause cell death. (6,7,14) This research indicates that even without including immune system pathologies, the presence of HIV (more precisely of gp120) sensitizes hepatocytes, increasing the damage due to the HCV infection. (Figure 3) There is also indication that the presence of surface proteins from both viruses (gp120 from HIV and E2 from HCV) triggers the production of the pro-inflammatory cytokine IL-8 in a p38-dependent, N F-B-independent manner. (15)

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HIV & HCV in end-stage liver disease

Effect of HAART on the immune response to HCV

When Highly Active Anti-Retroviral Therapy (HAART) was first introduced, many of the compounds used had significant hepatotoxicity. Nowadays, many first-line HAART agents have an acceptable liver safety profile and are acceptable as treatment during HIV/HCV coinfection.
(16)

Conclusions
HIV/HCV coinfection is still at a very high prevalence and has major effects on survival and quality of life. Nevertheless, the advent of liver-friendlier HAART to control HIV replication and damage and of direct acting antivirals against HCV allow us to look forward to mitigating, at least, the effect of this deadly virus combination.

Bibliography
1 WHO; UNAIDS; UNICEF. Progress report 2011: Global HIV/AIDS response. World Health Organization, November 2011. Disponivel em: <http://www.who.int/hiv/pub/proress_report201 1/summary_en .pdf>. 2 PETROVIC, L. M. HIV/HCV co-infection: histopahtologic findings, natural history, fibrosis, and impact of antiretroviral treatment: a review article. Liver Int, p. 598-606, 2007. 3 WHEELER, M. D. Endotoxin and Kupffer cell activation in alcoholic liver disease. Alcohol Research & Health, v. 27, n. 4, p. 300-306, 2003. 4 PAGE, E. E.; NELSON, M.; KELLEHER, P. HIV and hepatitis C coinfection: pathogenesis and microbial translocation. Cur Opin HIV AIDS, v. 6, p. 472-477, 2011. 5 KINUGASA, T. et al. Claudins regulate the intestinal barrier response to immune mediators. Gastroenterology, v. 118, n. 6, p. 1001-1011, 2000. 6 VLAHAKIS, S. R. et al. Human immunodeficiency virus-induced apoptosis of human hepatocytes via CXCR4. J Infect Dis, v. 188, n. 10, p. 1455-1460, 2003. 7 BABU, C. K. et al. HIV induces TRAIL sensitivity in hepatocytes. PLoS ONE, v. 4, n. 2, p. e4623, 2009. 8 KRNER, C. et al. Hepatitis C coinfection enhances sensitization of CD4+ T-cells towards Fas-ind uced apoptosis in viraemic and HAART-controlled HIV-1-positive patients. Antivir Ther, v. 16, p. 1047-1055, 2011.

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9 CARUNTU, F.; BENEA, L. Acute hepatitis C virus infection: Diagnosis, pathogenesis, treatment. J Gastrointestin Liver Dis, v. 15, n. 3, p. 249-256, 2006. 10 ROSEN, H. R. Hepatitis C Pathogenesis: Mechanisms of viral clearance and liver injury. Liver Transplant, v. 9, n. 11, Suppl 3, p. S35-S43, 2003. 11 CENTERS FOR DISEASE CONTROL AND PREVENTION. Hepatitis C -STD Treatment Guidelines 2006, 2006. Disponivel em: <http ://www.cdc.gov/std/treatment/2006/hepatitisc. htm>. 12 REVIE, D.; SLAHUDDIN, S. Z. Human cell types important for Hepatitis C Virus replication in vivo and in vitro. Old assertions and current evidence. Virol J, v. 8, p. 346, 2011. 13 DANDEKAR, S.; GEORGE, M. D.; BUMLER, A. J. Th 17 cells, HIV and the gut mucosal barrier. Cur Opin HIV AIDS, v. 5, p. 173-178, 2010. 14 JANG, J. Y. et al. HIV infection increases HCV-induced hepatocyte apoptosis. J Hepatol, v. 54, n. 4, p. 612-620, 2011. 15 BALASUBRAMANIAN, A.; GANJU, R. K.; GROOPMAN, J. E. Hepatitis C Virus and HIV envelope proteins collaboratively mediate interleukin-8 secretion through activation of p38 MAP kinase and SHP2 in hepatocytes. J Biol Chem, v. 278, n. 37, p. 35755-35766, 2003. 16 JONES, M.; NEZ, M. HIV and hepatitis C co-infection: the role of HAART in HIV/hepatitis C virus management. Cur Opin HIV AIDS, v. 6, p. 546-552, 2011.

Figures

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HIV & HCV in end-stage liver disease

Figure 1: Basic liver structure. From Frevert et al, PLoS Biology, 2005

Figure 2 Microbial translocation as a factor in acceleration of cirrhosis. From Page et al, 2011.

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HIV & HCV in end-stage liver disease

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HIV & HCV in end-stage liver disease

Figure 3 Increase in TRAIL and TRAIL receptors increases cell death. From Babu et al, 2009

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