Recovery from acute hepatitis B virus (HBV) infection occurs in 95% of adult-acquired infections. A 32-bp deletion in CCR5 (CCR5Δ32), which encodes for a nonfunctional receptor, increases the likelihood of recovery. Using 181 subjects with persistent HBV infection and 316 who had recovered, we tested the hypothesis that an epistatic interaction between functional polymorphisms in RANTES (a CCR5 ligand) and CCR5 impacts recovery. Specific models designed to assess individual contributions of compound genotypes demonstrated that the only combination associated with recovery from an HBV infection was RANTES −403A with CCR5Δ32 (odds ratio 0.36, p = 0.02). Because the phenotypic consequence of −403A is reported to be higher levels of RANTES, we propose a model in which excess RANTES in combination with low CCR5 favors recovery from an HBV infection, which will require validation through functional testing.

When infected with hepatitis B virus (HBV)3 as adults, most persons recover and develop protective Abs. However, ∼5% of adults remain chronically infected with HBV and are at risk for developing end-stage liver disease and hepatocellular carcinoma (1). Hepatitis B recovery occurs more often in individuals who develop a broad and strong T cell response rather than in those with a weak and narrowly focused response (2), but the genetic basis for differences in adaptive immunity remains poorly understood.

CCR5 influences the migration and activation of cells that express the receptor, including granulocytes, macrophages, immature dendritic cells, CD8+ lymphocytes, and Th1 lymphocytes (3). The gene encoding CCR5 consists of a single open reading frame producing a single transcript. A 32-bp deletion (CCR5Δ32) in this gene leads to a functionally null allele, which was previously identified in 10–15% of Caucasians (4). We found this deletion to be associated with recovery from acute HBV infection (5).

RANTES (CCL5), a ligand for CCR5, is a Th1 chemokine that promotes T cell activation and proliferation. The binding of RANTES to its alternate receptor, CCR1, has been shown to up-regulate the inflammatory response during sepsis (6) and to increase recruitment of NK cells to the liver in an autoimmune hepatitis mouse model (7). The RANTES gene has several known polymorphisms, including two functional promoter polymorphisms at positions −403 (G→A) and −28 (C→G), both of which associate with increased RANTES expression (8, 9, 10). These variants have been associated with several diseases, including HIV, asthma, sarcoidosis, and type 1 diabetes (9, 10, 11, 12, 13). Haplotypes composed of these two polymorphisms along with two others, the intronic variant INT1.1 T→C and a 3′ untranslated region variant 524 T→C, associate with levels of HIV RNA (14).

We hypothesized that epistatic interactions between functional RANTES polymorphisms and CCR5 genotype may affect the likelihood of recovery from an acute HBV infection. To test this hypothesis, we genotyped the RANTES polymorphisms −403, −28, Int1.1, and 524 (Fig. 1) in our Caucasian cohort, which has well-defined HBV outcomes and known CCR5 genotypes from an earlier study (5).

FIGURE 1.

Schematic diagram of RANTES gene and relative location of the coding regions (▪), untranslated regions (▨), and polymorphisms. The RANTES haplotypes are listed below the figure.

FIGURE 1.

Schematic diagram of RANTES gene and relative location of the coding regions (▪), untranslated regions (▨), and polymorphisms. The RANTES haplotypes are listed below the figure.

Close modal

The subjects in this study were the same ones that we had previously genotyped for CCR5Δ32 (5). They were Caucasian participants in one of the following ongoing studies: 1) Multicenter AIDS Cohort Study, which is a study of 5622 gay men enrolled in one of four U.S. cities between 1984 and 1985 and between 1987 and 1991 (15); 2) Multicenter Hemophilia Cohort Study, a prospectively followed cohort of patients with hemophilia, von Willebrand’s disease, or a related coagulation disorder from 16 comprehensive hemophilia treatment centers enrolled between 1982 and 1986, as previously described (16), and 3) Hemophilia Growth and Development Study, which is a continuing study of 333 children and adolescents with hemophilia enrolled between March 1989 and May 1990 (17). The majority of the subjects were from the Multicenter AIDS Cohort Study (80%), with the Hemophilia Growth and Development Study and Multicenter Hemophilia Cohort Study each contributing 10%. Informed consent was obtained from all participants.

To investigate our hypothesis, a nested case-control design was used in which all individuals who had a persistent hepatitis B infection from one of the above cohorts were matched to two persons, from the same cohort, who recovered from an HBV infection, but were otherwise similar with regard to nongenetic factors. Matching criteria included geographic location and factors that have been associated with HBV recovery, including age within 10 years, gender, and HIV-1 status (18). In this study, there were 190 subjects with a persistent HBV infection matched to 336 who had recovered; thus, for 44 persistently infected persons, only one match was available. Of these, RANTES genotyping was successful in 181 and 316 individuals with viral persistence and recovery, respectively. Informed consent was obtained from all participants, and this study was approved by the Institutional Review Board at participating institutions.

Subjects were considered persistently infected with HBV if their serum or plasma tested positive for hepatitis B surface Ag (HBsAg) at two visits separated by a minimum of 6 mo. Testing for Abs against hepatitis B core Ag (anti-HBc) and HBsAg (anti-HBs) was performed as needed to exclude primary HBV infection. Individuals with HBV recovery were positive for anti-HBc and anti-HBs without the presence of HBsAg at two time points separated by a minimum of 6 mo. All initial tests were performed on serum at the time of entry into the cohort study. HBV status of HIV-positive subjects was determined before antiretroviral therapy (including lamivudine) was available.

All serum specimens were stored at −70°C before testing. HIV type 1 Ab testing was done by enzyme immunoassay with reactive results confirmed as positive by Western blotting (15, 16). HBsAg, anti-HBs, and anti-HBc testing was done using commercially available kits, according to the manufacturer’s specifications (AUSZYME, AUSAB, and CORZYME, respectively; Abbott Laboratories).

For all the considered RANTES polymorphisms, samples were genotyped using a predeveloped TaqMan allelic discrimination assay (Applied Biosystems). PCR was conducted with mixes consisting of 5 ng of genomic DNA, 2.5 μl of Taqman master mix, 0.0625 μl of 40× assay mix, and ddH2O up to 5 μl of final volume. The following amplification protocol was used: denaturation at 95°C for 10 min, followed by 40 cycles of denaturation at 92°C for 15 s and annealing and extension at 60°C for 1 min. After PCR, the genotype of each sample was attributed automatically by measuring the allelic specific fluorescence on the ABI PRISM 7900 Sequence Detection Systems using the SDS 2.2.2 software for allelic discrimination (Applied Biosystems).

All polymorphisms in this study were in Hardy-Weinberg equilibrium, which was assessed for each single nucleotide polymorphism (SNP) using the χ2 test with 1 degree of freedom. Allele frequencies for RANTES were calculated and compared between those with viral recovery and persistence using conditional logistic regression (SAS Institute; version 10). An odds ratio (OR) >1 was associated with persistence and <1 with recovery. RANTES haplotypes were inferred from the genotypes in the study population and were constructed using a program designed for population-based studies, PHASE v 2.0 (http://www.stat.washington.edu/stephens/phase.html) (19) (Fig. 1). Value of p < 0.05 was considered significant in all analyses. Specific models were constructed to determine individual contributions from genotype combinations.

No significant differences were detected between those with viral persistence and recovery in terms of the matched, nongenetic factors (median age of 31.5, 100% male and 69% HIV infected). None of the individual RANTES genotypes was associated with recovery from HBV infection (Table I). Homozygosity for these SNPs was also not associated with HBV outcomes (data not shown). Similarly, none of the RANTES haplotypes was significantly associated with HBV recovery; the haplotype −403A, −28G, In1.1C, 524T was more common in those with HBV recovery (OR 0.45), but it did not reach statistical significance (p = 0.11).

Table I.

Allelic frequencies (%) of RANTES genotypes and haplotypes stratified by HBV recovery and persistence

HBV Recovery n = 316HBV Persistence n = 181pa
Genotype    
 −403G 81.3 80.5 NS 
 −28C 96.9 98.3 NS 
 In1.1 T 86.7 85.8 NS 
524T 90.3 87.3 NS 
Haplotypes−403,−28, In1.1, 524    
GCTT 81.2 80.3 NS 
ACTT 4.9 5.6 NS 
ACCT 0.5 0.3 NS 
ACCC 9.9 12.1 NS 
AGCT 3.3 1.7 NS 
HBV Recovery n = 316HBV Persistence n = 181pa
Genotype    
 −403G 81.3 80.5 NS 
 −28C 96.9 98.3 NS 
 In1.1 T 86.7 85.8 NS 
524T 90.3 87.3 NS 
Haplotypes−403,−28, In1.1, 524    
GCTT 81.2 80.3 NS 
ACTT 4.9 5.6 NS 
ACCT 0.5 0.3 NS 
ACCC 9.9 12.1 NS 
AGCT 3.3 1.7 NS 
a

NS, p > 0.05.

We next examined each of these RANTES SNPs in combination with CCR5Δ32 or CCR5 wild type using the CCR5 genotype data previously generated in the same cohort (5). For these univariate analyses, the reference group for each of these combinations included those with neither or only one of the genotypes in the combination. As expected from our prior study (5), most of the RANTES combinations with CCR5Δ32 had ORs favoring HBV recovery (0.46–0.58) due to the favorable effect of CCR5Δ32; however, two of the combinations had lower ORs (Table II). The presence of at least one copy of RANTES403A, a SNP that leads to increased RANTES expression, in combination with CCR5Δ32 had an OR for recovery from an HBV infection of 0.36 (95% confidence interval (CI) 0.16–0.83, p = 0.02). The compound genotype RANTES 524C and CCR5Δ32 had a similar OR of 0.38. Because RANTES 524C is always found with RANTES403A (Fig. 1) and the converse is not true, this finding with 524C is probably due to its tight linkage disequilibrium with RANTES403A.

Table II.

Percentage of subjects with each genotype or genotype combination stratified by HBV outcome

GenotypeHBV Recoveryan = 316HBV Persistencean = 181ORb95% CIp
CCR5Δ32c 23.7 14.3 0.51 0.31–0.85 0.009 
      
403G/Δ32 22.5 13.8 0.53 0.31–0.89 0.02 
403A/Δ32 10.8 3.9 0.36 0.16–0.83 0.02 
403G/WTd 94.6 97.8 2.38 0.78–7.24 0.13 
403A/WT 33.3 36.5 1.15 0.80–1.67 0.45 
28G/Δ32 2.5 1.7 0.58 0.15–2.34 0.45 
28C/Δ32 22.9 14.5 0.55 0.33–0.91 0.02 
28G/WT 5.4 3.4 0.51 0.18–1.41 0.19 
28C/WT 97.1 99.4 5.78 0.72–46.1 0.1 
In1.1 T/Δ32 23 14.3 0.53 0.32–0.88 0.01 
In1.1 C/Δ32 7.3 3.3 0.46 0.18–1.14 0.09 
In1.1 T/WT 96.2 98.3 2.21 0.6–8.12 0.23 
In1.1 C/WT 24.3 26.9 1.12 0.74–1.69 0.6 
524C/Δ32 4.7 1.6 0.38 0.11–1.32 0.13 
524T/Δ32 23.0 14.1 0.53 0.32–0.88 0.02 
524C/WT 18.3 22.8 1.35 0.86–2.12 0.2 
524T/WT 96.8 97.3 1.0 0.33–3.04 1.0 
GenotypeHBV Recoveryan = 316HBV Persistencean = 181ORb95% CIp
CCR5Δ32c 23.7 14.3 0.51 0.31–0.85 0.009 
      
403G/Δ32 22.5 13.8 0.53 0.31–0.89 0.02 
403A/Δ32 10.8 3.9 0.36 0.16–0.83 0.02 
403G/WTd 94.6 97.8 2.38 0.78–7.24 0.13 
403A/WT 33.3 36.5 1.15 0.80–1.67 0.45 
28G/Δ32 2.5 1.7 0.58 0.15–2.34 0.45 
28C/Δ32 22.9 14.5 0.55 0.33–0.91 0.02 
28G/WT 5.4 3.4 0.51 0.18–1.41 0.19 
28C/WT 97.1 99.4 5.78 0.72–46.1 0.1 
In1.1 T/Δ32 23 14.3 0.53 0.32–0.88 0.01 
In1.1 C/Δ32 7.3 3.3 0.46 0.18–1.14 0.09 
In1.1 T/WT 96.2 98.3 2.21 0.6–8.12 0.23 
In1.1 C/WT 24.3 26.9 1.12 0.74–1.69 0.6 
524C/Δ32 4.7 1.6 0.38 0.11–1.32 0.13 
524T/Δ32 23.0 14.1 0.53 0.32–0.88 0.02 
524C/WT 18.3 22.8 1.35 0.86–2.12 0.2 
524T/WT 96.8 97.3 1.0 0.33–3.04 1.0 
a

Numbers in columns represent percentage of people with each particular genotype combination.

b

OR calculated with univariate conditional logistic regression. OR <1 is associated with viral recovery.

c

Comparison of CCR5Δ32 (heterozygous or homozygous) compared with CCR5WT/WT irrespective of RANTES genotypes.

d

WT, wild type.

In the univariate analysis of RANTES −403A and CCR5Δ32 combination, the reference group included those with CCR5Δ32 with the wild-type RANTES (−403G), making it difficult to determine the independent associations of CCR5Δ32 with the mutant and wild-type RANTES −403 polymorphisms. To overcome this, we constructed a more specific model to determine the independent contribution of each genotype combination for these two polymorphisms. One combination served as the reference group and was composed of the individuals who were homozygous for the wild-type RANTES (−403G/G) and the wild-type CCR5. The variables in the model were each of the other possible genotype combinations (Table III). We found that only individuals with both minor variants, RANTES −403A and CCR5Δ32, were significantly more likely to have HBV recovery (OR 0.36, 95% CI 0.16–0.85, p = 0.02). The combination of CCR5 wild type and at least one copy of RANTES −403A was not associated with clearance (OR 1.37). Individuals with CCR5Δ32, but no copies of RANTES −403A (i.e., −403G/G), had an OR for recovery from an HBV infection that was intermediate between the other two (OR 0.70, 95% CI 0.38–1.31, p = 0.26). Thus, in this model, having CCR5Δ32 without the minor RANTES variant was no longer statistically significantly associated with HBV recovery. Likewise, the minor RANTES variant, −403A, without CCR5Δ32 also was not associated with HBV outcome. When the other RANTES promoter polymorphisms were included in such a model, the combinations with CCR5Δ32 were not significantly associated with HBV recovery (data not shown).

Table III.

Model with each of the RANTES −403 and CCR5 genotype combinations

GenotypeORa95% CIp
403G/G and CCR5 WT/WTb (reference group) N/A N/A 
403Ac and CCR5 WT/WT 1.37 0.91–2.07 0.13 
403G/G and any CCR5Δ32 0.70 0.38–1.31 0.26 
403Ac and any CCR5Δ32 0.36 0.16–0.85 0.02 
GenotypeORa95% CIp
403G/G and CCR5 WT/WTb (reference group) N/A N/A 
403Ac and CCR5 WT/WT 1.37 0.91–2.07 0.13 
403G/G and any CCR5Δ32 0.70 0.38–1.31 0.26 
403Ac and any CCR5Δ32 0.36 0.16–0.85 0.02 
a

OR <1 is associated with viral recovery.

b

WT, wild type.

c

Includes −403A and −403A/A.

The data presented in this study demonstrate a protective epistatic effect of CCR5Δ32 and RANTES −403A in recovery from a HBV infection. In our previous study that did not include RANTES polymorphisms (but used the same study subjects) (5), we demonstrated that CCR5Δ32 conferred a protective effect against HBV. We now show that it is the combination of CCR5Δ32 and RANTES −403A that is most protective against this virus, in which individuals with this compound genotype were nearly three times as likely to recover compared with those who had neither of these genotypes. Interestingly, RANTES −403A without the CCR5Δ32 was not associated with HBV recovery and CCR5Δ32 without RANTES −403A showed only weak, nonsignificant protection. This is the first demonstration of an interactive effect between a RANTES and CCR5 compound genotype, one that makes sense given the receptor/ligand relationship of these two molecules. We cannot totally eliminate the possibility that the interaction with CCR5Δ32 is due to RANTES 524C rather than RANTES −403A, because RANTES 524C is in tight linkage disequilibrium with RANTES −403A.

Two other studies have examined the effects of RANTES promoter polymorphisms on HBV outcomes, but neither looked at interactive effects with CCR5 genotypes. In a Korean study, 350 people with HBV recovery and 607 with a persistent HBV infection were genotyped for the −403 RANTES polymorphism, but no association was present (20). A second Korean study genotyped the −28 polymorphism in addition to the −403, and no association was detected (21). These data are consistent with our data in that we did not see an association with HBV clearance without the presence of CCR5Δ32, an allele that is virtually missing in Asian populations.

HIV coinfection in nearly 70% of our subjects was carefully considered in our study, because CCR5Δ32 and RANTES polymorphisms are known to affect HIV outcomes. In our previous study, we found that the association with CCR5Δ32 and HBV recovery was not affected by HIV status (5). In our current study, we also conclude that the effect of CCR5Δ32 and RANTES −403A on HIV infection cannot explain the effect of these variants on HBV recovery based on the following: 1) those with viral recovery and persistence were matched on HIV status in our study, and 2) HBV infection occurred before HIV infection in nearly all cases, so the outcome of HBV infection (i.e., clearance/persistence) is determined before acquiring HIV (22). For those few cases in which the HIV infection did occur first, it is unlikely that immunosuppression from HIV played a significant role in these results because the HBV status was determined at study entry, before clinical HIV-induced immunosuppression. Of note, the status of the HBV infection was established before availability of oral antiretroviral agents with activity against both HIV and HBV; thus, none of the individuals had been treated for HIV or HBV before the time the HBV infection status was determined.

It is intriguing to consider why the compound genotype of CCR5Δ32 and the RANTES403A would enhance recovery from an HBV infection because CCR5 is not a receptor for HBV. Characteristics of the cellular and cytokine profiles in the Con A-induced hepatitis mouse model give some clues to understanding this finding (7). In this model, NK cells do not infiltrate the liver in the wild-type mouse upon Con A treatment, but they do accumulate in the liver of CCR5-deficient mice upon Con A treatment, a situation that would theoretically enhance an immune response and aid in the spontaneous recovery of HBV infection. The study showed that CCR5 deficiency associates specifically with elevated RANTES expression in the mouse liver, but not that of other CCR5 ligands. The authors postulated that the increase in liver RANTES subsequently leads to enhanced interactions between this chemokine and its alternative receptor, CCR1, an interaction that results in recruitment of NK cells. Indeed, upon treatment of the mice with anti-RANTES Ab, there was a significantly reduced recruitment of NK cells into the liver after Con A administration. A second observation from the mouse work, potentially relating to HBV clearance, is that Con A treatment of CCR5-deficient mice leads to NK cell activation and subsequent production of IFN-γ. Like the anti-RANTES treatment, treatment of the mice with anti-IFN-γ mAbs reduced cellular and cytokine responses in this model, underscoring the importance of IFN-γ in the response.

So, why do individuals with CCR5Δ32 have an even further advantage when combined with RANTES −403A? Data from cell lines demonstrate that the RANTES −403A promoter polymorphism leads to higher levels of RANTES expression (8). Thus, it is possible that individuals with the protective compound genotype may produce high amounts of RANTES in the liver upon infection with HBV, which is more likely to interact with CCR1 when CCR5 levels are low (i.e., presence of CCR5Δ32), leading to an increase in NK cell recruitment to the liver. And, based on the enhanced IFN-γ production in the absence of CCR5 in the mouse model, the decrease in CCR5 due to the presence of the null CCR5Δ32 allele may lead to increased activation of the NK cells to produce IFN-γ and thus aid in the immune response to HBV.

A limitation to our study is that we were not able to obtain RANTES levels from the livers or serum of our participants at the time of their hepatitis B infection. It would be of particular interest to determine the level of CCL5 in liver tissue of patients with compared to those without the CCR5Δ32 + RANTES −403A genotype because several mouse studies have demonstrated differences in CCL5 levels in affected tissues as opposed to systemic alterations (7, 23, 24). Liver biopsies are not performed on individuals who are disease free (i.e., cleared the virus or have persistent infection without disease symptoms), so a hepatitis B transgenic mouse model may be required to approach such studies.

In summary, these data are the first to demonstrate an epistatic effect of RANTES −403A and CCR5Δ32 on the outcome of an infectious disease. Data from a mouse model provide a potential explanation for why this compound genotype favors recovery from HBV infection. If valid, the data would support an important role for NK cells in recovery from an HBV infection.

We thank Abbott Laboratories for donating HBsAg and anti-HBs kits, and all cohort participants for making this study possible.

The authors have no financial conflict of interest.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Data in this manuscript were collected by the Multicenter AIDS Cohort Study, with centers (principal investigators) at The Johns Hopkins University Bloomberg School of Public Health (Joseph B. Margolick, Lisa Jacobson); Howard Brown Health Center and Northwestern University Medical School (John Phair); University of California, Los Angeles (Roger Detels); and University of Pittsburgh (Charles Rinaldo). The Multicenter AIDS Cohort Study is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute and the National Heart, Lung, and Blood Institute (UO1-AI-35042, 5-MO1-RR-00722 (GCRC), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041). Website located at http://www.statepi.jhsph.edu/macs/macs.html

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The publisher or recipient acknowledges rights of the U.S. Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.

1

This work was supported by National Institutes of Health Grant DA00441 and by the investigators in the Pathogenesis of Infectious Diseases Award from the Burroughs Wellcome Fund (to C.L.T.). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract N01-CO-12400. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Multicenter Hemophilia Cohort Study is supported by National Cancer Institute Contract N02-CP-55504 with RTI International. Hemophilia Growth and Development Study is supported by the Bureau of Maternal and Child Health and Resources Development (MCJ-060570), the National Institute of Child Health and Human Development (NO1-HD-4-3200), the Centers for Disease Control and Prevention, and the National Institute of Mental Health. Additional support has been provided by grants from the National Center for Research Resources of the National Institutes of Health to the New York Hospital-Cornell Medical Center Clinical Research Center (MO1-RR06020); Mount Sinai General Clinical Research Center, New York (MO1-RR00071); University of Iowa Clinical Research Center (MO1-RR00059); University of Texas Health Science Center, Houston (MO1-RR02558); and R01-HD-4-1224.

3

Abbreviations used in this paper: HBV, hepatitis B virus; anti-HBc, Ab to hepatitis B core Ag; anti-HBs, Ab to hepatitis B surface Ag; CI, confidence interval; HBsAg, hepatitis B surface Ag; OR, odds ratio; SNP, single nucleotide polymorphism.

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