Journal of Hepatology
Volume 42, Issue 1 , Pages 150-152, January 2005

Contrary to HIV, hepatitis C virus is not associated with erythrocytes in vivo

  • Salima Sadallah

      Affiliations

    • Department of Research, University Hospital Basel, Basel, Switzerland
    • ,
  • Markus Heim

      Affiliations

    • Department of Research, University Hospital Basel, Basel, Switzerland
    • Department of Medicine, University Hospital Basel, Basel, Switzerland
    • ,
  • Christoph Hess

      Affiliations

    • Department of Research, University Hospital Basel, Basel, Switzerland
    • ,
  • Thomas Klimkait

      Affiliations

    • Institute of Microbiology, University of Basel, Basel, Switzerland
    • ,
  • Manuel Battegay

      Affiliations

    • Department of Medicine, University Hospital Basel, Basel, Switzerland
    • ,
  • Jürg A. Schifferli

      Affiliations

    • Department of Research, University Hospital Basel, Basel, Switzerland
    • Department of Medicine, University Hospital Basel, Basel, Switzerland

published online 02 September 2004.

Article Outline

Keywords: Immune complexes, HCV, HIV-1, Erythrocytes

 

To the Editor:

We have recently found that in chronically HIV-1 infected patients, a fraction of HIV-1 in blood was associated with erythrocytes [1]. In some of these patients HIV-1 was undetectable in plasma but present on erythrocytes indicating that the erythrocyte-pool of viruses may be a blood marker for ongoing replication of HIV-1. The adherence of HIV-1 to erythrocytes is best explained by the formation of virus-antibody complexes, followed by complement activation with C3 deposition and binding to the complement receptor 1 of erythrocytes (CR1=CD35, or ‘immune adherence’ receptor)[2], [3]. There are some possible similarities between chronic HIV-1 and HCV infections: (1) both viruses are detected in plasma in the presence of specific antibodies, i.e. virus-antibody complexes are formed [2], [4]; (2) the erythrocytes CR1 are diminished in both infections suggesting ‘consumption’ due to excessive binding of immune complexes [5], [6] and (3) relapses occur even when the viral loads in plasma have been reduced to undetectable levels, indicating that plasma levels are poor indicators of persistent viral replication. Using in situ RT-PCR on blood smears, Lotz et al have suggested that HCV may be found associated to erythrocytes in chronically infected patients, thus erythrocyte HCV might represent an unrecognized pool of viruses indicating ongoing infection [7].

Here, we analyzed whether HCV is associated with erythrocytes in chronic HCV infected patients (90), before and after interferon therapy (62 paired samples) and in patients with double HCV/HIV infections (10 patients). Erythrocytes purification and HIV-1 RNA detection was performed as previously described (1). HCV-and HIV-1-RNA on erythrocytes and plasma were quantified using the COBAS Amplicor system (Roche diagnostic). As seen in Fig. 1, most of the erythrocytes samples were negative (i.e. <600IU/mL) or borderline positive but mostly below 10% of the total viral load, suggesting that HCV does not bind significantly to erythrocytes in vivo. Indeed, a low apparent binding might be due to a contamination from plasma. In addition, all the samples (40) taken after successful interferon therapy, i.e. with negative HCV-RNA in plasma, were also negative for HCV‐RNA associated with erythrocytes. The specificity of no or very low binding of HCV to erythrocytes was confirmed in the HIV/HCV coinfected patients where the negligible amounts of HCV in the erythrocyte fractions contrasted with a high load of HIV-1 in the same fractions (in 5/12 samples: more than 50% of HIV-1 were on erythrocytes; not shown). The discrepancies with Lotz data can be explained by the technical shortcomings of the in situ PCR technique, bound to create a whole series of artefacts.We do not think that our washing steps dissociated HCV-antibody complexes from erythrocytes, since the same procedure did not dissociate HIV-antibody complexes and other immune complexes in past studies [1], [8]. The blood smear method of Lotz may have produced an in vitro association of HCV with erythrocytes.

  • View full-size image.
  • Fig. 1. 

    HCV-RNA in whole blood compared to erythrocytes pool in HCV chronically infected patients. The erythrocyte pool of HCV-RNA (IU/ml: International Units per milliliter) was compared to the total amount of HCV-RNA (IU/ml) recovered in whole blood (plasma+erythrocytes). Sixty-five of the samples had a negative erythrocyte HCV viral load i.e. below the threshold (bold line: 600IU/ml) of the quantitative PCR assay. The 57 positive samples had an erythrocyte HCV viral load distributed as follow: 46 below 1% of the total viral load—10 below 10% of the total viral load. Only one sample had a HCV RNA erythrocyte viral load just above 10%.

In conclusion, unlike HIV-1, no significant association of HCV-RNA with erythrocytes was detected in HCV infected patients. HIV-1 and HCV ICs might differ in their complement-activating properties because of differences in the distribution of immunoglobulins on the viruses i.e. steric conformation inducing formation of the lattice and/or the class (subclass) of antibodies involved.. One is tempted to speculate that the avoidance of the erythrocyte-shuttle system might favor the association of plasma HCV/anti-HCV complexes with IgM rheumatoid factors that become deposited in tissues such as kidney and skin [9], [10].

Back to Article Outline

Acknowledgements 

This work was supported by the Swiss National Sciences Foundation 0032-66708-01 and Roche Pharma Switzerland. We would like to thank Mrs Nadine Doppler from the Institute of Microbiology, University of Basel for the HCV and HIV‐1 RNA quantification on erythrocytes and in the plasma.

Back to Article Outline

References 

  1. Hess C, Klimkait T, Schlapbach L, et al. Association of a pool of HIV-1 with erythrocytes in vivo: a cohort study. Lancet. 2002;359:2230–2234
  2. Montefiori DC, Graham BS, Zhou JY, et al. Binding of human immunodeficiency virus type 1 to the C3b/C4b receptor CR1 (CD35) and red blood cells in the presence ofenvelope-specific antibodies and complement. J Infect Dis. 1994;170:429–432
  3. Horakova E, Gasser O, Sadallah S, et al. The adherence of HIV to Erythrocytes is complement dependent in an in vitro model. [Abstract 217]. Int Immunopharmacol. 2002;2:
  4. Chen M, Sallberg M, Sonnerborg,et A, et al. Limited humoral immunity in hepatitis C virus infection. Gastroenterology. 1999;116:135–143
  5. Lach-Trifilieff E, Marfurt J, Schwarz S, Sadallah S, Schifferli JA. Complement receptor 1 (CD35) on human reticulocytes: normal expression in systemic lupus erythematosus and HIV-infected patients. J Immunol. 1999;162:7549–7554
  6. Kanto T, Hayashi N, Takehara T, et al. Low expression of erythrocyte complement receptor type 1 in chronic hepatitis C patients. J Med Virol. 1996;50:126–134
  7. Lotz G, Szalay F, Firneisz G, et al. Localization of hepatitis C virus RNA on human erythrocytes by RT in situ PCR technique. Scand J Gastroenterol. 2002;37:578–584
  8. Madi N, Steiger G, Estreicher J, Schifferli JA. Abnormal immune adherence and elimination of HBs Ag/Ab complexes in patients with acquired immunodeficiency syndrome. J Immunol. 1992;148:723–728
  9. Sansonno D, Gesualdo L, Manno C, Schena FP, Dammacco F. Hepatitis C virus-related proteins in kidney tissue from hepatitis C virus-infected patients with cryoglobulinemic membranoproliferative glomerulonephritis. Hepatology. 1997;25:1237–1244
  10. Trendelenburg M, Schifferli JA. Cryoglobulins in chronic hepatitis C virus infection. Clin Exp Immunol. 2003;133:153–155

PII: S0168-8278(04)00364-2

doi:10.1016/j.jhep.2004.07.027

Journal of Hepatology
Volume 42, Issue 1 , Pages 150-152, January 2005

Article Tools

* Image Usage & Resolution