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Frequency of the HIV-protective CC chemokine receptor 5-Δ32/32 genotype is increased in hepatitis C
Reported by Jules Levin
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This study data was reported first at the 8th Retrovirus Conference in 2001 and is being poblished now in the Gastroenterology journal (June 2002, Vol 122, Number 7). Ranier Woitas reported this study both at Retrovirus and in this journal (University of Bonn, Bonn, Germany) and the article was received for publication on June 26, 2001).
"...given the results of our study, possible adverse effects of CCR5 inhibitors on other viral infections such as HCV, which are frequently associated with HIV
infection, must be considered carefully..."
But I think this is preliminary data and a clinical study in patients should yield more relevant answers. In an editorial in this journal, Jeffrey Laurence said: it is also possible that interactions between HCV and CCR5-mediated processes could affect therapeutic outcomes to interferon alfa and ribavirin. These agents, apart from their anti-viral role, may modulate cytokine production, thereby indirectly mitigating HCV disease because, for example, interferon alfa may decrease fibrosis without altering HCV viral load. If CCR5-dependent processes are involved in the fibrotic stage of HCV disease, then 32 CCR5 patients might have more dramatic responses to interferon alfa. Several factors suggest a role for CCR5 in clearance of an acute hepatic infection such as HCV. The liver has the highest proportion of CD56+ NK cells and NK-like
CD3+ NKT cells of any organ, and these cells produce the CCR5 ligands MIP-1,-1 and RANTES. As noted above, innate immunity mediated by NK cell
cytolysis and interferon- production, occurring within hours of a primary HCV infection, could eliminate HCV-infected cells before assembly and release of new virions. CCR5 may also play a role in the subsequent recruitment of lymphocytes to the liver.
Definitions: an allele is one member of a pair or series of genes that occupies a specific position on a specific chromosome. Homozygous is when one has the same alleles at one or more gene loci on homologous chromosome segments. A heterozygote (or hetrozygous) is when one has different alleles at one or more corresponding chromosome loci.
Unlike the case with HIV infection, HCV does not require CCR5 expression for cell entry. Thus, hepatitis C infection provides an excellent opportunity to study whether altered CCR5 expression because of CCR5-Δ32 deletion has any effect on the course and outcome of the infection. To address this issue, we determined the frequency of the mutant CCR5-Δ32 allele, as well as HCV- and HIV-related parameters, in a cross-sectional analysis of all anti-HCV-positive, anti-HIV-positive, and anti-HCV/HIV doubly positive white patients attending our outpatient department between May, 1999, and August, 2000.
Study Results: The homozygous CCR5-Δ32 mutation was significantly more frequent in anti-HCV-positive patients than in the healthy background population, as well as in the patients with HIV- or HCV/HIV infection (P < 0.02). The heterozygous mutation was most frequent in patients with HCV/HIV infection (NS). The gene frequency of the CCR5-Δ32 mutation was significantly higher in the anti-HCV-positive patients (16.0%) than in the healthy controls (8.3%, P = 0.017, 2 = 5.744) and in the HIV-infected patients (9.3%, P = 0.041, 2 = 4.192). The frequency of the CCR5-Δ32 allele was 10.7% and 18.0% in the anti-HCV-positive subgroups with negative and positive HCV RNA by PCR, respectively (NS). The CCR5-Δ32 mutant gene was also slightly more frequent in the HCV/HIV-coinfected group (12.7%), but this difference from our reference group did not reach statistical significance. We found an important, unexpectedly high number of patients (12 of 153 individuals) who were homozygous for the CCR5-Δ32 mutation in our group with HCV monoinfection.
Patients with the wild-type receptor gene were more likely to be HCV RNA negative: Although only a single CCR5-Δ32 homozygous patient (8.3%) had undetectable HCV RNA, the percentage of patients with a negative PCR was more than 3-fold higher in the patients who were either heterozygous or homozygous for the CCR5 wild-type gene (28% [7/25] and 29.3% [34/116%], respectively). However, this difference did not reach statistical significance.
Among the viremic patients of the anti-HCV-positive group, HCV loads were significantly higher in the CCR5-Δ32 homozygous patients than in the wild-type
homozygous patients (median: 32.3 million copies/mL and 5.1 million IU/mL vs. 5.7 million copies/mL and 0.90 million IU/mL, respectively; P = 0.045.
This finding suggests a pathophysiological link between loss of CCR5 expression and HCV infection. Patients in this study with HCV or coinfection were mostly hemopliliacs. Thus, we cannot completely exclude a contribution from the different routes of virus infection between our groups, which puts hemophiliac patients in particular under the selection pressure of multiple viral exposures. But the authors say that selection bias alone, however, is unlikely to account for the increased frequency of the CCR5-Δ32 mutation in the anti-HCV-seropositive group for several reasons:
Distribution of CCR5 genotypes
WT/WT, group of patients with homozygosity for the CCR5 wild-type allele; 32/WT, group of patients with heterozygosity for CCR5 wild-type and the CCR5-Δ32 deletion; 32/32, group of patients with homozygosity for the CCR5-Δ32 deletion.
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Study Abstract: A homozygous 32-base pair deletion in the CCR5 gene (CCR5-Δ32) protects against human immunodeficiency virus infection (HIV). However, the role of this mutation in other infections, such as hepatitis C virus (HCV) infection, has not been defined. We determined the frequency of the CCR5-Δ32 mutation by polymerase chain reaction in anti-HCV+ (n = 153), anti-HIV+ (n = 102), and anti-HCV+/HIV+ (n= 130) white patients as well as in 102 healthy blood donors. Then, HIV and HCV loads, aminotransferases, and CD4 and CD8 cell counts were compared between the resulting subsets of CCR5-Δ32/wild-type heterozygotes, CCR5-Δ32, and wild-type homozygotes, respectively.
RESULTS: Twelve of 153 (7.8%) anti-HCV-seropositive patients and 1 of 102 (1.0%) healthy blood donors were CCR5-Δ32 homozygous, whereas CCR5-Δ32 homozygosity was absent in anti-HIV+ and anti-HCV+/HIV+ patients (P < 0.001). The frequency of the CCR5-Δ32 allele was higher in the anti-HCV+ (16.0%,
P < 0.05) and anti-HCV+/HIV+ (12.7%, NS) patients than in healthy blood donors (8.3%) and anti-HIV+ patients (9.3%), respectively. HCV/HIV coinfected had a high rate of heterozygous mutation, that is 1 deletion (25%). Anti-HCV+ CCR5-Δ32 homozygotes occurred 3 times more frequently than expected from the Hardy-Weinberg equation (P < 0.0001) and had significantly higher HCV loads than wild-type patients (P = 0.045). The authors concluded thatthe increased prevalence of CCR5-Δ32 homozygosity associated with increased viral loads in patients with chronic hepatitis C suggests that the CCR5-Δ32 mutation may be an adverse host factor in hepatitis C.
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