8th Annual Retrovirus Conference
Late Breakers
Chicago, Feb 4-8 2001

CCR5-D32 Mutation -- Protective Against HIV, but Bad for Hepatitis C Virus?
(Abstract 499)

     R. P. Woitas*, G. Ahlenstiel, H. H. Brackmann, B. Matz, J. K. Rockstroh*, and U. Spengler. Inst. of Experimental Hematology, Virology, Univ. of Bonn, Germany

In light of the findings reported from the study below, one concern I have that may be speculation on my part is that CCR5 antagonists for HIV may do harm to people with HCV.

CCR5 has been identified as the major co-receptor for the entry of M-tropic variants of HIV-1. Polymorphisms in the CCR5 gene can modulate the natural history of HIV. Indeed homozygosity of a 32-base- pair (bp) deletion (CCR5-D32) (present in 1% of a Caucasian population) is associated with resistance to HIV-1 infection. However, the role of the CCR5-D32 mutant allele for other infections such as hepatitis C virus (HCV) has not been defined yet.

We determined the frequency of the mutant CCR5-D32 allele by PCR in a cohort of 151 anti-HCV- positive, 105 anti-HIV-positive and 130 HIV/HCV-coinfected patients. Patients were stratified according to their CCR5 genotypes (CCR5-D32/CCR5-D32 vs. CCR5-D/wild-type (WT) vs. WT/WT) and compared with respect to HIV and HCV viral loads, aminotransferases, CD4 and CD8 cell counts. Statistical analysis was performed using ANOVA,C2and non-parametric tests.

Results: The CCR5 WT/WT genotype was present in 116/151 (76.8%), 86/105 (81.9%), and 97/130 (74.6%) of the patients with HCV single, HIV single and HIV/HCV double infection, respectively.D32/WT heterozygotes were found in 25/151 (16.6%), 19/105 (18.1%), and 33/130 (25.4%) of patients in each group, respectively. 10/ 151 (6.6%) patients with HCV exhibited theD32/D32 genotype, while homozygous patients were completely absent in both HIV-infected groups (p < 0.001). Furthermore, the distribution of theD32/D32 genotype in anti- HCV-positive patients was threefold higher than predicted by the Hardy-Weinberg equation (p < 0.001). HCV loads were significantly higher in HIV/HCV-coinfected patients of all subgroups than in patients with HCV alone (p < 0.05). TheD32/D32 homozygous patients had significantly higher HCV loads than the WT/WT or the heterozygousD32/WT genotype (p < 0.01). Aminotransferases did not vary with respect to the CCR5 genotype but were significantly higher in patients with HIV/HCV coinfection (p < 0.05).

Our data confirm that homozygosity for the CCR5-D32 mutation is protective against HIV infection. However, the increased frequency ofD32/D32 genotypes among patients with HCV infection together with increased HCV loads in CCR5-D32 homozygotes suggests unfavourable effects of this mutation for the course of HCV infection.

Mutation That Slows HIV May Play a Role in Hepatitis C
     By LAWRENCE K. ALTMAN, New York Times - February 7, 2001

CHICAGO, Feb. 6 - Five years ago, scientists discovered that some people had a genetic mutation in their cells that could either protect them against infection from the AIDS virus or significantly slow the course of AIDS.

Today, German scientists reported an odd twist to the mutation story. At the eighth annual retrovirus meeting here, they reported evidence suggesting that the mutation could have a negative effect for people infected with the hepatitis C virus, which causes potentially fatal liver disease.

Further research is needed. But the findings could have potential importance in the epidemiology of hepatitis C infections and the development of anti-HIV drugs directed at the mutation, Dr. Rainer Woitas, the head of the German team from the University of Bonn, said in an interview.

The mutation involves the deletion of part of a gene on the surface of cells. The gene, CCR5, is one of the major receptor sites for the entry of HIV.

About 1 percent of Caucasians inherit a double dose of the mutation that usually confers resistance to HIV infection. People who inherit only one dose of the mutation and become HIV-infected often take about two years longer to develop AIDS than infected people without the mutation.

Dr. Woitas, a specialist in internal medicine with a long interest in hepatitis C, came to his findings in an unusual way. After other scientists in the United States and Europe discovered the mutation's effect in HIV in 1996, Dr. Woitas theorized that the mutation might also play a role in hepatitis C.

So he and his colleagues conducted tests to determine the frequency of the mutation among four groups. One group of 153 people had the hepatitis C virus only. A second group of 102 people had HIV only. A third group of 130 people had both infections. A fourth group of 102 people were blood donors with no known infections who were included for purposes of a scientific control.

Dr. Woitas's team confirmed the finding that the double dose form of the mutation protected against HIV infection. But 12 of the 153, or 7.8 percent, in the hepatitis-C-only group had the mutation, and statistical tests showed it was three times more common than expected.

People with the mutation also had levels of hepatitis C virus in their blood about four times higher than in those without the mutation.

People with higher levels of a virus in the blood often fare worse than those with lower levels. But because the German studies were not developed to measure outcomes, Dr. Woitas said that additional studies were needed to do cument whether people with the mutation fared worse, and that they were underway.

Dr. Woitas theorized that the mutation interfered with the immune system in some unknown way to have an adverse effect on hepatitis C and the protective effect on HIV.

The study also led Dr. Woitas to speculate that the immune system might in some cases successfully defend against the hepatitis C virus and lose the antibodies. If so, he said, scientists would need to develop a new test to determine who had been infected with hepatitis C, since current tests screen for the infection by using antibodies to the virus.

Dr. David Ho, the head of the Aaron Diamond AIDS Research Center in Manhattan, said that if an experimental drug was developed to counter the mutation and tested in humans, scientists would have to screen for hepatitis C infection among the recipients to avoid possibly worsening the liver infection.

The Centers for Disease Control and Prevention also announced a campaign developed to "break the back" of the AIDS epidemic by cutting the number of new infections in half by 2005, largely by identifying Americans who carry HIV but do not know it.

The effort, announced today, is based on the fact that most AIDS infections are spread by people who do not realize they have HIV.

The agency believes that if these people knew they were infected, they would be more careful to protect others, and they would also take AIDS drugs that would probably make them less likely to transmit the virus.

     Copyright 2001 The New York Times Company

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