| Human Molecular Genetics | Pages |
©1999 Oxford University Press |
Genetics of HIV-1 infection: chemokine receptor CCR5 polymorphism and its consequences
Introduction
Variation In The CCR Coding Region
CCR5-[Delta]32
Additional coding region variants of the CCR5 gene
Variation In The Promoter Region Of CCR5
Variable expression of CCR5
Characterization of the CCR5 promoter
Linkage disequilibrium between CCR5 promoter region and CCR2-64I
Additional polymorphism in the CCR5 promoter region
Summary
Acknowledgements
References
Genetics of HIV-1 infection: chemokine receptor CCR5 polymorphism and its consequences
Received June 18, 1999; Accepted June 28, 1999
The chemokine receptor gene, CCR5, has become a central theme in studies of host genetic effects on HIV-1 pathogenesis ever since the discovery that the CCR5 molecule serves as a major cell surface co-receptor for the virus. A growing number of genetic variants within the coding and 5[prime] regulatory region of CCR5 have been identified, several of which have functional consequences for HIV-1 pathogenesis. Here we review the CCR5 literature describing CCR5 polymorphism and the functional ramifications that several of these variants have on HIV-1 infection and progression to AIDS. The multiplicity of CCR5 genetic effects on HIV-1 disease underscores the critical importance of this gene in controlling AIDS pathogenesis and provides the logic for development of therapeutic strategies that target the interaction of HIV-1 envelope and CCR5 in HIV-1 associated disease.
INTRODUCTION
Chemokine receptors are cell surface molecules that bind peptide ligands called chemokines, thereby inducing migration of the receptor-bearing cells toward injured tissues that secrete chemokines into the bloodstream. It is through this mechanism that leukocytes are recruited into sites of inflammation (1,2). A number of host cell surface molecules are used by infectious agents to gain entry into cells and it is now clear that HIV-1 enters cells through an interaction involving chemokine receptors (3-7). So-called `R5' isolates of HIV-1 use the chemokine receptor CCR5 to infect macrophages and primary T cells, and these isolates are present early after seroconversion indicating their role in initiation of HIV-1 infection (8-12). The eventual use of CXCR4 by isolates of HIV-1 (X4 isolates, which infect primary T cells and T cell lines) closely corresponds to the onset of AIDS, although R5 isolates do persist throughout the entire course of infection (8-12). The central role of CCR5 in HIV-1 infection demands a clear understanding of the relationship between this receptor and virus, including the genetic alterations of the CCR5 gene that play a role in controlling infection and disease progression.
VARIATION IN THE CCR5 CODING REGION
CCR5-[Delta]32
The CCR5 gene has been mapped to the short arm of chromosome 3 amongst a group of genes that encode multiple chemokine receptors (13). Soon after CCR5 was shown to behave as a co-receptor along with CD4 for HIV-1, the mutant allele CCR5-[Delta]32, which is characterized by a 32 bp deletion in the single coding exon of the gene, was identified in Caucasians (14-16). CCR5-[Delta]32 does not produce a functional protein (15), explaining the near-complete protection against HIV-1 infection in individuals homozygous for the allele. Rare cases of HIV-1 infection in the absence of CCR5 have been reported (17-19), however, suggesting that X4 isolates can sometimes initiate HIV-1 infection. Individuals homozygous for CCR5-[Delta]32 display no clinical symptoms and appear to be healthy. Other homologous chemokine receptors bind an overlapping set of chemokine ligands and may compensate for the absence of CCR5 in individuals homozygous for CCR5-[Delta]32 (2).
Another effect of CCR5-[Delta]32 includes slower progression to AIDS (by 2-4 years on average) after HIV-1 seroconversion in individuals heterozygous for the mutation (14,20-22). The frequency of the CCR5-[Delta]32/+ genotype is ~20% in Caucasians, so this genotype has a significant population effect on progression to AIDS. The CCR5-[Delta]32/+ genotype results in markedly diminished levels of CCR5 on the cell surface and low expression of CCR5 correlates with reduced infection of T cells by R5 isolates of HIV-1 in vitro (23). Rather than simply a gene dosage effect, formation of CCR5-[Delta]32/CCR5 heterocomplexes causes CCR5 to be retained in the endoplasmic reticulum resulting in reduced cell surface expression of the wild-type molecule (24). The CCR5-[Delta]32/+ genotype is also associated with protection from AIDS-related lymphoma, a non-Hodgkin's B cell malignancy (25,26). Although the mechanism for this protection is not clear, B cells do express CCR5 on their cell surfaces, and RANTES, one of four chemokine ligands of CCR5, is mitogenic for B cells (26). It is possible that RANTES may play a role in lymphoma expansion via CCR5 before immune surveillance has a chance to eliminate the malignant cells. If so, then diminished levels of CCR5 in CCR5-[Delta]32/+ heterozygotes may be advantageous by indirectly controlling B cell expansion.
Additional coding region variants of the CCR5 gene
The CCR5-[Delta]32 mutation is estimated to have occurred ~700-2000 years ago (27,28) and since that time has increased to a frequency of 13% in some Northern European populations (27,29). It is absent in Africans and most Asian populations, and its frequency in African Americans (f = 0.02) can be explained by admixture. The rapid increase in frequency of this mutation over a relatively short period of time suggests that the CCR5-[Delta]32 mutation has been subject to positive selection. If indeed the CCR5-[Delta]32 mutation has been (and perhaps still is) under selective pressures, then it is likely that other mutations resulting in severe functional alterations will also be subject to selection. Twenty-one additional alleles of the CCR5 coding region have been described (30,31), two of which we identified recently and have not been published previously (S63C and R319H).Mutations defining two of the alleles cause premature termination of translation (C101X and 893delC; Table 1). Frequencies of the variants were 0.04 or lower and, among patients screened, no samples were homozygous for any of these variants. Thus, the epidemiological consequence of these variants on HIV-1 infection or progression to AIDS could not be evaluated. Among the 22 total variants of the CCR5 gene, however, 16 are protein altering (non-synonymous) and only four are synonymous variants. The high predominance of codon-altering variants (18/22 or 82%) is consistent with an adaptive accumulation of function-altering CCR5 alleles (32).
Table 1. Genetic variations of the CCR5 gene
| Variant | Nucleic acid substitution | Frequency | Reference | |
| Caucasians | African Americans | |||
| I12Ta | A25C | <1% | 0 | 31 |
| C20Sa | T58A | <1% | 0 | 31 |
| A29Sa | G85T | NT | 1.5% | 31 |
| I42Fa | A124T | <1% | NT | 31 |
| L55Qa | T164A | 3-4% | <1% | 30, 31 |
| R60S | G180T | NT | 1% | 31 |
| S63C | A187T | <1% | 0 | unpublished data |
| A73Va | C218T | <1% | 0 | 31 |
| S75S | T215C | 0 | 1.3% | 31 |
| C101X | T303A | NT | <1% | 31 |
| I164I | C492A | <1% | NT | 31 |
| [Delta]32 (185) | D32 | 10.0% | 1.9% | |
| L215S | C664T | 0 | <1% | 30 |
| R223Qb | G668A | 1.6% | <1% | 30, 31 |
| 228delK | 680del3 | <1% | 0 | 31 |
| 299 (FS)b | 893delC | 0 | 0 | 30 |
| V300V | C900A | <1% | 0 | 31 |
| G301V | G902T | <1% | 0 | 31 |
| R319H | G956A | <1% | 0 | unpublished data |
| P332P | C996T | 0 | <1% | 30 |
| A335V | C1004T | <1% | 2.5% | 30, 31 |
| Y339F | A1016T | 0 | 2.6% | 30, 31 |
aAlleles tested for CCR5 ligand signaling (34); see text.
bFound at 3-5% in Asian populations (30).
Each of six variants (I12T, C20S, I42F, L55Q, A73V and C101X) in cohorts studied were identified in individuals carrying the CCR5-[Delta]32 allele on the opposite haplotype (31,33). Only the single type of CCR5 variant molecule is expressed on the cell surfaces of these individuals since CCR5-[Delta]32 does not encode a cell surface molecule. Individuals expressing C20S, I42F or C101X were negative for HIV-1, in spite of high risk for having been exposed to the virus. Individuals expressing I12T, A73V, and L55Q were infected with HIV-1, although in the case of I12T, it is possible that a chemokine receptor other than CCR5 was used to gain entry to the cell (see below). Whereas it was observed that three CCR5 variants heterozygous for CCR5-[Delta]32 avoided HIV-1 infection after likely exposure, influence of these variants on HIV-1 infection would be required to conclude that they are protective.
Recently, we analyzed ligand signaling plus influence on HIV-1 infection for six of the naturally occurring variants (indicated by `a' in Table 1) located within the N-terminal third of the CCR5 gene, including I42F and C20S (34). Binding of the normal CCR5 ligands (RANTES, MIP-1[alpha] and MIP-1[beta]) to variants with substitutions in the first extracellular domain (I12T, C20S and A29S) was either completely abrogated or severely reduced, corresponding with an inability of these variants to transduce a chemotactic signal to requisite ligands. The I12T and C20S variants were also unable to function as co-receptors for R5 isolates of HIV-1, suggesting that these variants radically alter conformation of the CCR5 molecule. Since I12T was originally identified in an HIV-1-infected individual who was heterozygous for CCR5-[Delta]32, it is possible that the individual with I12T/CCR5-[Delta]32 was not resistant to R5 tropic HIV-1 infection. Alternatively, this individual may have become infected by an X4 isolate of HIV-1 using CXCR4 as a portal of entry (17-19). A29S supported HIV-1 infection in vitro, but failed to bind chemokine ligands efficiently. The phenotypic effects of variants located in the first and second transmembrane domains (I42F, L55Q and A73V) were quite different from those in the first extracellular domain, having 4-8-fold enhanced affinity for chemokine. These variants transduced a chemotactic response to RANTES, MIP-1[alpha] and MIP-1[beta], but they did not exhibit the typical attenuation of response at high ligand concentrations, perhaps resulting from their strong affinity for the chemokine ligands. Cells expressing all three transmembrane variants supported HIV-1 infection.
VARIATION IN THE PROMOTER REGION OF CCR5
Variable expression of CCR5
Regulation of CCR5 expression is likely to be complex, but an understanding of mechanisms controlling its expression could be of significant therapeutic value in AIDS prevention (35-39). Expression of CCR5 is restricted to activated and memory T cells, monocytes/macrophages, microglial cells (40-43) and, to a lesser extent, B cells (26). CCR5 cell surface expression is highly variable even in individuals who are homozygous for the normal allele of the gene (CCR5-+/+) (23). While it is not clear whether heterogeneity in protein expression correlates with differences in HIV-1 infection in vivo, peripheral blood mononuclear cells from individuals with the genotype CCR5-+/[Delta]32 are not as easily infected with R5 isolates of HIV-1 in vitro as are individuals with CCR5-+/+ (15). Individuals with the genotype CCR5-+/[Delta]32 express lower levels of CCR5 correlating with relatively low viral loads (44) and slow progression to AIDS (14,20-22). Such observations have stimulated studies of the upstream promoter region of the CCR5 gene that have addressed functional, genetic and epidemiological aspects of the region.
Characterization of the CCR5 promoter
The original partial length genomic clone of CCR5 showed that it specified a single open reading frame (ORF) (45). Comparison of this sequence with two cDNA clones (46,47) indicated the presence of a 1.9 kb intron between position -11 and -12 relative to the start of translation. Additional studies have verified the organization of CCR5 to include a short non-coding exon (43 bp), a 1.9 kb intron, followed by an exon that contains 11 bp of the 5[prime]-UTR and the complete ORF (48,49). Using 5[prime]-RACE, Mummidi et al. (50) described two additional 5[prime] untranslated exons and one additional intron. Exons 2 and 3 are not interrupted by an intron and, in agreement with the other reports (47-49), exon 4 (that containing the ORF) and exon 3 (exon 1 in the previous reports) are transcribed within several RNA isoforms of CCR5. There are two distinct promoters of CCR5, one of which lies upstream of exon 1 (Pu), and another that lies downstream in the region between intron 1 and exon 2 (Pd)(50). The identification and approximate location of Pd was concurrent among all studies characterizing the CCR5 promoter region (48-51). The downstream promoter appears to be much stronger than the upstream promoter in monocytic and lymphocytic cell lines, as well as CD4+ T cells (48-51). Sequence motifs similar to consensus sequences for a variety of transcription factors have been identified in the Pd promoter region and mutational analysis of several such sequences indicated their importance in transcription of CCR5 (51). Thus, polymorphism in this region could potentially disrupt transcription factor binding motifs, accounting for some of the heterogeneity in CCR5 expression among individuals (52).
Several numbering systems for the CCR5 promoter region have been used throughout the literature. In order to standardize the nomenclature at this locus, a numbering system in which the first nucleotide of the translation start site is designated as position 1, and the nucleotide immediately upstream of this as position -1, was recently proposed at the CCR5 AIDS symposium held at the NCI-FCRDC, Frederick, MD, on April 30, 1999.
Linkage disequilibrium between CCR5 promoter region and CCR2-64I
Genes encoding the CCR1-CCR5 molecules are clustered in the p21.3-p24 region of chromosome 3 (13,45,53). A human genomic DNA contig within this region (143 068 bp) was sequenced as part of the Advanced Genome Sequence Analysis Course at Cold Spring Harbor Laboratory, NY (GenBank accession no. U95626; unpublished data). The contig shows that CCR2 and CCR5 are separated by only ~14 kb (Fig. 1), explaining in part the near complete linkage disequilibrium between the two genes (54). The variant CCR2-64I in the first transmembrane region of CCR2 has been shown to be associated with relatively slow progression to AIDS (54,55) and this protection is genetically independent of that conferred by CCR5-[Delta]32. It seems unlikely that the CCR2-64I allele has a direct effect on AIDS progression because: (i) CCR2 is used as a co-receptor by only rare isolates of HIV-1 (5,6,56), and (ii) CCR2-64I encodes a product that binds chemokine ligand, and mediates both calcium mobilization signalling and R5 tropic HIV-1 infection as efficiently as wild-type CCR2 molecules (57). These observations along with the physical proximity of CCR2 and CCR5 have led to the speculation that CCR2-64I is simply tracking by linkage disequilibrium another variant of CCR5 (55), in particular since all CCR2-64I bearing haplotypes are wild-type or normal with respect to the CCR5 coding region (54). These observations provide further impetus for studying effects of variability in the regulatory region of CCR5.
Figure 1. Map illustrating positions at which variations have been identified in the coding regions of CCR2, CCR5 and 5[prime] upstream region of CCR5. The numbering system used, designates the first nucleotide of the translation start site of CCR5 as position 1, and the nucleotide immediately upstream of this as position -1.
The C->T transition variant at position 59 653 [according to GenBank accession no. U95626, position 927 according to the numbering system of Mummidi et al. (50), and position -1835 according to the new numbering system, which will be used throughout the remainder of this review] located in intron 2 of CCR5 was found in 100% linkage disequilibrium with CCR2-64I (55). Although no data indicating a functional role in the control of CCR5 expression has been observed for this variant (termed `-1835T' herein), it could explain the effect on AIDS progression seen in individuals with CCR2-64I. We have examined 984 individuals for both CCR2-64I and -1835T (CCR5P-927T) and found that all CCR2-64I-bearing haplotypes contained -1835T, but -1835T was also found infrequently on a haplotype carrying CCR2+ (16/230) (58). Nine of these were seroconverters and preliminary analysis of the nine hinted toward AIDS protection (relative hazard = 0.49 for AIDS-1993 definition), although significance was not reached. On the other hand, -1835T in the absence of CCR2-64I was associated with slightly accelerated disease progression in another study, although not significantly so (59). The question is not settled and further studies examining genetic associations and potential functional effects of -1835T must be addressed to determine whether it has a protective role in AIDS progression.
Additional polymorphism in the CCR5 promoter region
Several studies have addressed the possibility that polymorphism in the CCR5 promoter region can account for some of the variability in progression to AIDS among HIV-1 infected individuals by altering levels of CCR5 transcription (55,58-60). As mentioned in the previous section, two studies have addressed the effect of variation at position -1835T (previously 927) on progression to AIDS (55,59), but -1835T is in strong linkage disequilibrium with the CCR2-64I allele, so it is difficult to determine which variant (if either) is truly protective.
A number of additional variants in the 5[prime]-UTR of CCR5 have been identified (50,58,59) and seven of these distinguish four common promoter region alleles identified in Caucasian and African American samples (positions -2733, -2554, -2459, -2135, -2132, -2086 and -1835 in Fig. 1 and Table 2). The four alleles that we previously designated CCR5P1, CCR5P2, CCR5P3 and CCR5P4 (58) (Table 2) were observed at frequencies of 0.56, 0.085, 0.014 and 0.354, respectively, in Caucasians. (CCR5P1-P4 were originally defined by the variant sites -2554, -2135, -2132, -2086 and -1835, which completely distinguish the four common alleles defined by the seven positions listed above.) In order to determine the effects of these four alleles on progression to AIDS, it was necessary to identify haplotypes composed of the neighboring variants CCR2(+/64I) and CCR5(+/[Delta]32), since both alter rates of progression to AIDS (14,20-22,54,55). Six relatively common haplotypes composed of three loci, (i) the CCR2 coding region variant CCR2(+/64I); (ii) the four promoter region alleles consisting of variants located from positions -2733 through -1835; and (iii) the CCR5 coding region variant CCR5(+/[Delta]32), were identified. The protective alleles CCR2-64I and CCR5-[Delta]32 arose independently on two haplotypes containing the same promoter allele, CCR5P1. However, CCR5P1 is found most frequently (f = 0.36) on a haplotype containing wild-type CCR5 (CCR5-+) and wild-type CCR2 (CCR2-+). Survival analyses in which individuals were partitioned by genotypes indicated presence of three distinct groups: (i) those homozygous for the haplotype CCR2+-CCR5P1-CCR5+ who developed AIDS most rapidly; (ii) those with genotypes containing at least one copy of CCR5-[Delta]32 or CCR2-64I, who had appreciably delayed onset of AIDS; and (iii) those with any other genotypic combination who developed AIDS at a rate intermediate between the susceptible and protected genotypes (58). Thus, homozygosity for CCR5P1 may explain some of the variability in CCR5 expression known to occur among individuals who do not carry the CCR5-[Delta]32 mutation (23).
Table 2. CCR5P alleles
| New | -2733 | -2554 | -2459 | -2150 | -2136 | -2135 | -2132 | -2115 | -2086 | -2078 | -2048 | -1951 | -1835 |
| Ref. 50a | 29b | 208b | 303b | 612 | 626 | 627b | 630 | 647 | 676b | 684b | 714 | 811 | 927b |
| GenBank no. U95626c | 58755 | 58934 | 59029 | 59338 | 59352 | 59353 | 59356 | 59373 | 59402 | 59410 | 59440 | 59537 | 59653 |
| P1.1 | A | G | A | A | C | C | C | C | A | T | C | G | C |
| P1.w2 | G | - | - | n | n | - | n | n | - | n | n | n | - |
| P1.w3 | - | - | - | n | n | - | n | n | - | n | n | n | T |
| P2.1 | - | - | G | - | - | T | - | - | - | - | - | - | - |
| P3.1 | - | T | G | - | - | T | T | - | - | - | - | - | - |
| P4.1 | - | T | G | - | - | T | - | - | G | - | - | - | - |
| P5.1 | - | - | G | G | - | T | - | - | - | - | - | - | - |
| P6.1 | - | - | - | - | - | - | T | - | - | C | - | - | - |
| P7.1 | - | - | - | - | A | - | - | - | - | - | - | - | - |
| P8.1 | - | - | G | - | - | T | - | A | - | - | - | - | - |
| P9.1 | - | - | G | - | - | T | - | - | - | - | - | A | - |
| P10.1 | - | T | G | - | - | T | - | - | G | - | G | - | - |
| P11.w1 | - | - | G | n | n | - | n | n | - | n | n | n | - |
aIdentified by multiple labs.
bAccording to Mummidi et al. (50).
cAccording to GenBank accession no. U95626.
Very similar results were observed for the A/G variant at position -2459 (position 59 029 of GenBank accession no. U95626) (60), which we now recognize as a component of CCR5P1. In this study, individuals who were homozygous for -2459G (found on CCR5P2-P4) progressed to AIDS 3-8 years more slowly than those who were homozygous for -2459A (found on CCR5P1). Of the 417 individuals typed for position -2459 by McDermott et al. (60), 342 were also typed for CCR5P in the Martin et al. (58) study. Unfortunately, results from these two studies should not be considered as confirmatory since there was a high level of overlap in the patients tested by both groups and the variants tested were in very strong, if not complete linkage disequilibrium.
The simplest conclusion to be drawn from the described epidemiological data is that CCR5P1 (including -2459A) has more efficient promoter activity than the other promoter alleles, leading to a relatively increased number of CCR5 receptors for HIV-1 on cell surfaces. Quantitative analysis of CCR5 on peripheral blood mononuclear cells from healthy volunteers representing two distinct genotypes, homozygosity for the haplotype CCR2+-CCR5P1-CCR5+ or homozygosity for CCR2+-CCR5P4-CCR5, were studied for functional differences regarding CCR5 expression. Cells representing each of these genotypes did not vary significantly in assays measuring (i) mean concentrations of CCR5; (ii) efficiency of promoting a luciferase reporter construct; and (iii) infectivity by R5 or R5/X4 strains of HIV-1 (58). It is possible that the effect of CCR5P1 is too weak to be detected by the assay conditions used, for it is subtle enough only to be observed epidemiologically in CCR2+-CCR5P1-CCR5 homozygotes. McDermott et al. (60), on the other hand, observed 45% lower promoter activity from a promoter allele containing the -2459G variant than that containing the -2459A variant. The CCR5 promoter regionsegment used in their reporter-gene construct included all the variant sites described by Martin et al. (58), so it follows that the promoter allele used in their construct was CCR5P1. If so, this would suggest that there may indeed be a difference between the CCR5P1 and other promoter region alleles.
More recently, we have used gel-shift assays to determine whether the variants at each of the five positions -2554 (G/T), -2459 (A/G), -2135 (C/T), -2086 (A/G) and -1835 (C/T) differ in their ability to bind nuclear factors in T cell extracts (52). A clear difference in binding of one or more nuclear factors to oligonucleotides representing the two variants at position -2554 (-2554T found on the P4 allele and -2554G found on the P1 allele) was observed. This provides enticing, albeit weak, support for the hypothesis that CCR5 promoter region variation is responsible for the epidemiological effects observed in the AIDS cohorts.
SUMMARY
The central role of the CCR5 molecule in HIV-1 infection has led to a wealth of information over the past 3 years characterizing its functional and genetic properties. The mutant CCR5-[Delta]32 allele has been shown to provide almost complete protection against HIV-1 infection in homozygous individuals. Heterozygous individuals also exhibit slower progression to AIDS after seroconversion, and protection from AIDS-related lymphoma. Additional variants, most of which are codon-altering, have also been identified, and functional analysis suggests that some of these variants may protect against HIV-1 infection as a result of severe alteration in the conformation of the molecule. The promoter region of the CCR5 gene has been characterized by several groups, and it appears that polymorphisms in this region may have an effect on AIDS progression, possibly due to their effect on levels of CCR5 expression. These studies should prove useful not only in predicting outcome to HIV-1 infection, but also in developing novel therapeutic strategies.
ACKNOWLEDGEMENTS
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 US Government. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract no. NO1-CO-56000.
REFERENCES
+To whom correspondence should be addressed. Tel: +1 301 846 1296; Fax: +1 301 846 1686; Email: obrien{at}ncifcrf.gov
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