HIV-HCV coinfection and liver cancer
Viral infections are recognized as important factors associated with cancer development worldwide. However, since only a small proportion of infected individuals develop cancer, cofactors related to the host's immune response or to the environment seems crucial in cancer pathogenesis. Viral oncogenesis involves sustained viral oncoprotein synthesis, leading to cell proliferation and eventually to transformation. In this context, disruption of cell cycle control with unrestrained cell division and growth and resistance to apoptosis play important roles. Sequential events in cell cycle control will be reviewed with emphasis on the role of cell cyclins and associated phosphokynases. These include interaction of extracellular growth factors with membrane-associated receptors, phosphokynase activation and signal transduction, translocation of cytoplasmatic transcription factors into the nucleus, activation of immediate early genes, cell division and action of cell cycle control proteins (pRB and p53) inducing cell cycle arrest or apoptosis.
HCV is responsible for the most important blood-borne infection, a relevant cause of chronic liver disease and cancer. In Brazil it is a significant public health concern, as sentinel studies show an overall 1.5% to 2% seroprevalence of HCV infection in the general population. Viral transmission routes are mainly blood-borne (associated to blood transfusions or IDU), though sexual intercourse, domestic non-sexual transmission and organ transplantation may also occur. HIV-HCV coinfection is common, results from shared mechanisms of acquisition and its prevalence is estimated as 30% to 40% in Europe and the USA, whereas Brazilian studies indicate 17.7% in São Paulo and 36.2% in Santos.
Although acute HCV infection is usually asymptomatic, 85% of cases develop persistent infection, ultimately leading to chronic hepatitis, cirrhosis and hepatocarcinoma. Risk factors for liver fibrosis in chronic HCV infection include duration of infection, male sex, older age at viral acquisition, severe alcohol intake, HIV coinfection, lower CD4+ cell count, overweight and diabetes. Among cirrhotic patients 1% to 4% develop liver cancer each year. Hepatocarcinoma is the most frequent primary liver cancer, runs 5th in incidence among men and 8th among women, but accounts for the 3rd cause of cancer mortality. Malignant disease is often fulminant, due to late diagnosis, poor response to chemotherapy and high recurrence rates after surgery or liver transplantation. Risk factors for HCV-associated liver cancer include male sex, older age, HBV or HIV coinfections, severe alcohol intake, overweight and diabetes.
HCV replication cycle will be reviewed including cell invasion after interaction with cell surface receptors, internalization of viral RNA, viral replication and protein synthesis, post-transcriptional protein processing, set up of the replicase complex, viral particle assembly and budding from the cell surface. So far the mechanisms of HCV oncogenesis are not well understood: there are no oncogenes in the viral genome, replication is totally intra-cytoplasmatic and the viral genome is not inserted into the cell DNA. Cancer development is thus believed to depend on interaction of viral proteins with the cell cycle and/or to result from continuous liver cell damage and regeneration (cell turnover). HCV core, NS3A and NS5A proteins have been shown to inhibit p21waf expression and p53 activity. In addition, HCV core protein inhibits cell apoptosis induced by TNF-alpha and Fas and NS5A transactivates cell cyclins and growth factors.
HIV-HCV coinfection induces significant changes in the natural history of HCV liver disease, rendering HCV persistence more likely, with higher levels of HCV viremia and faster progression of liver disease. This may be due to less effective anti-HCV CD4+ and CD8+ cell immune response, as well as to impaired dendritic cell function.
French studies have recently pointed out for a significant increase in HCV-related morbidity and mortality among people living with HIV/AIDS under HAART. Better knowledge about this infection and its relationship with cancer development is essential for the establishment of effective primary and secondary prophylaxis.
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06 Jan 2006
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