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The Role of the Immune System in Determining Viral Outcome after Hepatitis C Viral (HCV) Infection.

José Azócar, M.D., D.S.
Medical Director
Northgate Medical, Springfield

Infection by the hepatitis C virus (HCV) is a growing public health concern. In the general population the prevalence of HCV antibodies in the United States has been reported to be 1.8 %. However, this figure is higher in other countries or in populations at high risk for infection (1, 2, 3). After infection, 70 to 80 % of the infected subjects develop chronic viremia, characterized by the presence of HCV-RNA in plasma. Some of these subjects develop chronic liver disease, mainly cirrhosis of the liver and hepatocellular carcinoma several years after the initial infection (4). The remaining 20 to 30 % of the people infected by HCV are able to control the infection, clear the virus spontaneously, and remain free of liver disease, although positive for anti-HCV IgG in plasma (1, 4). It is generally accepted that genes within the Major Histocompatibility Complex (MHC) play a central role in the development of the immune response against HCV (5, 6). Several studies have addressed the issue of the association of Class II HLA alleles with the clinical outcome after initial HCV infection. However, which genes are associated with one outcome or another seems to depend on the ethnicity of the infected subject.

In Caucasians, spontaneous clearance of HCV has been described as being associated mainly with the HLA alleles DQB1*0301, DRB1*01, DRB1*0501, and DRB1*1101. In the same ethnic group, persistent infection has been associated with the DRB1*0301, DQB1*0201 and DRB4*0101 (5-8).

In African American subjects, however, viral clearance was mainly associated with the DQB1*0301 (9). In other ethnic groups, diverse associations have been made between HLA alleles and the outcome of HCV infection (10,11). In Hispanics a strong anti HCV immune reaction and viral clearance is associated with the Class II HLA allele DQB1-0501 (12), just the opposite of what occurs in Caucasians (5-8). How could the same allele be associated with different outcomes? In one ethnic group it is associated with chronic viremia, while in another it is associated with spontaneous viral clearance.

A primary cause for the difference in results published by different authors may be due to the great variability of the frequency of HLA alleles in different ethnic populations. However, Azocar et al. suggested that this might be the result of the linkage disequilibrium between certain class II genes and the other genes involved in the regulation of the immune response and clinical outcome after the initial HCV infection (12).

The variability in the association of HLA alleles and the response to HCV infection related to ethnicity requires further studies to rule out the possible role of Class II HLA alleles in HCV viremia, and should include studies of several genetic markers within the MHC in several ethnic groups or nationalities.


  1. Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, Kaslow RA, Margolis HS. The prevalence of hepatitis C infection in the United States, 1988 through 1994. N Eng J Med, 1999; 341: 556-562
  2. Frank C, Mohamed MK, Strickland GT, Arthur RR, Magder LS, Khoby El, Abdel-Wahab Y, Aly Ohn ES, Sallam I. The role of parenteral antischistosomal therapy in the spread of hepatitis C virus. Lancet, 2000; 355:887-891
  3. Memon MI, Memon MA. Hepatitis C: an epidemiological review. J Viral Hepat; 2002; 9: 84-100
  4. Lauer GM, Walker BD. Hepatitis C viral infection. N. Eng J. Med, 2001; 345: 41-52
  5. Thursz M, Yallop R, Goldin R, Trepo C, Thomas HC. Influence of the MHC Class II genotype on outcome of infection with hepatitis C. The Lancet 1999; 354: 2119-2124
  6. Eckels DD, Wang H, Bian TH, Tabatabai N, Gill JC. Imunobiology of hepatitis C virus (HCV) infection; the role of CD4 T cells in HCV infection. Immunol Rev, 2000; 174:90-7
  7. Alric L, Fort T, Isopet J, et al. Genes of the major histocompatibility complex class II influence the outcome of hepatitis C virus infection. Gastroenterology 1997;113:1675-1681.
  8. Cramp M.E., Carucci P, Underhill J et al. Association of Class II genotype and spontaneous clearance of hepatitis C viremia. J. Hepatol 1998; 29:207-13
  9. Thio CL, Thomas DL, Geodert JJ, et al. Racial differences in HLA class II association with hepatitis C virus outcomes. J Infect Dis 2001; 184:16-21
  10. Migaguchi S, Saito H, Ebinuma H, Morizante T, Ishii H. Possible association between HLA antigens and response to interferon in Japanese patients with chronic hepatitis C. Tissue Antigens 1997, 49:605-611.
  11. Vejbaesya S , Songsivilai S, Tanwendee T, Rachaibun S, Chantangpol R, Dharakul T. HLA association with hepatitis C viral infection. Hum Immunol 1999; 61: 348-353
  12. Azocar J, Clavijo O, Yunis EJ. MHC Class II Genes in HCV viral clearance of Hepatitis C Infected Hispanic patients. Hum Immun. In Press.
Copyright November 2002 – Hepatitis C Support Project - All Rights Reserved. Permission to reprint is granted and encouraged with credit to the Hepatitis C Support Project.

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