People with HIV and hepatitis C (HCV) coinfection may be able to take advantage of treatment with the new generation of HIV chemokine antagonists now in development, according to the results of a French study published in the Journal of Acquired Immune Deficiency Syndromes. The study found that density of the CCR5 chemokine receptor on CD4+ cells was not correlated with the severity of liver damage in coinfected patients, suggesting that downregulating CCR5 expression with drugs in order to prevent HIV entry into cells may not worsen the prognosis of people with HIV/HCV coinfection.
There has been considerable speculation that CCR5 antagonists might not be suitable for use by people coinfected with HIV and hepatitis C, and clinical trials of HIV chemokine antagonists under development by Pfizer, Schering Plough and GlaxoSmithKline plan to exclude people with HIV/HCV coinfection because of this fear. The concern is due to evidence that individuals with the delta 32 deletion in the CCR5 gene (which leads to little or no expression of the CCR5 receptor on the cell surface) have a higher prevalence of HCV infection, higher HCV viral load, higher ALT levels and greater liver fibrosis than people without this polymorphism.
However the CCR5 receptor may also play a role in the HCV disease process, through recruiting T-lymphocytes to the liver, where they are involved in the clearance of HCV during acute infection (a possible explanation for the higher prevalence of HCV in people homozygous for the CCR5-delta 32 deletion) and the generation of hepatic lesions in chronic HCV infection.
People with high CCR5 densities on T-lymphocytes might fight HCV infection more effectively, so the researchers set out to determine whether there are differences in hepatitis C disease severity in HIV/HCV coinfected patients according to levels of CCr5 expression on T-lymphocytes.
Flow cytometry was used to count CCR5 molecules on the surface of T-lymphocytes in 51 HIV/HCV coinfected patients recruited at the University Hospital of Montpellier in France. These were correlated with severity of liver disease.
Patients had a median duration of HCV infection of 18 years, as estimated by severity of liver disease and history of injecting drug use, and a median HCV viral load of 7.9 x 105 IU/ml. Sixteen per cent had no fibrosis, 43% had stage 1 fibrosis, 23% had stage 2 fibrosis, 12% had stage 3 fibrosis and 6% had cirrhosis. The median CD4 cell count was 329 cells/mm3 and 86% were taking antiretroviral therapy at the time of sampling.
No correlation was found between CCR5 density and HCV viral load, nor with ALT and AST levels. There was also no correlation between CCR5 density and fibrosis severity, speed of fibrosis progression or liver inflammation.
The researchers also looked at the stability of CCR5 density over time in ten patients using stored samples and found that during follow-up periods of between seven and 60 months, CCR5 density remained stable.
They state: “Our data argue against a key role in HCV infection of the variability in CCR5 expression among HCV/HIV-coinfected patients. These findings are reassuring based on the use of CCR5 antagonists to treat HCV/HIV coinfected patients.”
The simplest explanation for the lack of an effect of CCR5 variability, suggest the authors, is that other chemokine receptors compensate for the absence of CCR5 in determining the intensity of the anti-HCV response.
An alternative explanation, they say, is that lower CCR5 density, whilst down-regulating the anti-HCV response, also limits HIV replication and so limits the harmful effect of HIV on HCV activity.
Vincent T et al. T-cell surface CCR5 density is not correlated with hepatitis severity in hepatitis C virus/HIV-coinfected individuals: implications for the therapeutic use of CCR5 antagonists. J Acquir Immune Defic Syndr 38 (3): 305-309, 2005.