Frequencies of 32 base pair deletion of the (Δ32) allele of the CCR5 HIV-1 co-receptor gene in Caucasians: a comparative analysis

doi:10.1016/S1567-1348(02)00027-8

Infection, Genetics and Evolution

Volume 1, Issue 3, May 2002, Pages 201-205

https://doi.org/10.1016/S1567-1348(02)00027-8 Get rights and content

Abstract

The CCR5 gene encodes for the co-receptor for the major macrophage-tropics strains of human immunodeficiency virus (HIV-1), and a mutant allele of this gene (Δ32) provide to homozygotes a strong resistance against infection by HIV. The frequency of the Δ32 allele was investigated in 40 populations of 8842 non-infected subjects coming from Europe, the Middle-East and North Africa. A clear north–south decreasing gradient was evident for Δ32 frequencies, with a significant correlation coefficient (r=0.83). The main frequency value of Δ32 for Sweden, Norway, Denmark, Finland and Iceland (0.134) is significantly (χ²=63.818, P<0.001) highest than the Δ32 mean value, indicating that probably the Vikings might have been instrumental in disseminating the Δ32 allele during the eighth to the tenth centuries during historical times. Possibly variola virus has discriminated the Δ32 carriers in Europe since the eighth century AD, explaining the high frequency of the Δ32 allele in Europe today.

Introduction

The CCR5 gene product encodes a seven-transmembrane G-protein-coupled chemokine receptor, that serves as an entry port for primary human immunodeficiency virus (HIV-1) strains that infect monocytes and macrophages. The mechanism of resistance to repeated exposure by the virus has been provided by the identification in individuals of Caucasian origin of a null mutation of CCR5 (Liu et al., 1996, Samson et al., 1996, Dean et al., 1996): homozygotes for the 32 bp deletion (Δ32) in the gene segment encoding the second extracellular loop of CCR5 appear to resist infection. The 16 and 1% of healthy Europeans were reported to be heterozygous and homozygous for Δ32, respectively (Samson et al., 1996, Dean et al., 1996), and the mutant allele was not observed in black Africans or Japaneses. In North American Caucasians, the frequency of heterozygosity for Δ32 was 21.7%, and it was much less common in African–Americans (5.8%), Hispanics (6.9.%), and 0.6% in Asian–Americans (Zimmerman et al., 1997).

A high allele frequency of Δ32 was found among several Caucasian populations (Martinson et al., 1997, Libert et al., 1998, Stephens et al., 1998), leading to the most parsimonious hypothesis that the mutation occurred only once in the ancestry of the Caucasian ethnic group. After our two successive studies on the subject in France (Lucotte and Mercier, 1998a) and in Europe (Lucotte and Mercier, 1998b), we present here a comparative analysis on Δ32 frequencies (based on a total of 8442 unrelated non-infected control individuals from 40 populations) from Europe, the Middle-East and North Africa.

Section snippets

Molecular methods used

In most of the studies compiled here, extraction of DNA from blood samples and PCR amplification was performed as previously described in our own first study on the subject (Lucotte, 1997); after EcoRI restriction, the 735 bp PCR product using Samson et al. (1996) primers was cleaved into a common band of 332 bp for both alleles, and into a 403 bp product for the normal type (+) and a 371 bp for the mutant (Δ32) alleles.

Allelic frequencies in 40 populations

The Δ32 allele of the CCR5 gene was found in all the populations studied, but with some important difference in frequencies among countries. All the population tested (Table 1) showed no significant deviation from Hardy–Weinberg equilibrium. Fig. 1 shows the spatial distribution of Δ32 allele frequencies in the 40 populations studied.

From the 8442 individuals screened, the mean percentage of Δ32 is 7.7%. A significant genetic heterogeneity was observed among the population samples (χ²=365.985, P

Discussion

As suggested by previous authors (Martinson et al., 1997, Libert et al., 1998, Stephens et al., 1998), a northward–southward latitudinal gradient of Δ32 allele frequencies in Caucasians is established on a quantitative basis in our present comparative analysis, including more recent published studies. In this work we formally described the equation of the decreasing cline, and we analyzed in details the gradual decline in Δ32 frequencies among the successive steps of latitude north decrease in

References (25)

R. Liu et al.
Homozygous defect in HIV-1 co-receptors accounts for resistance of some multiply-exposed individuals to HIV-1 infection
Cell
(1996)
G. Lucotte
Frequencies of the CC chemokine receptor 5 Δ32 allele in various populations of defined racial background
Biomed. Pharmacother.
(1997)
G. Lucotte
Frequency analysis and allele map in favor of the Celtic origin of the C282Y mutation of hemochromatosis
Blood Cells Mol. Dis.
(2001)
G. Lucotte et al.
Δ32 Mutation frequencies of the CCR5 co-receptor in different French regions
C. R. Acad. Sci. Paris
(1998)
J.C. Stephens et al.
Dating the origin of the CCR5Δ32 AIDS-resistance allele by the coalescence of haplotypes
Am. J. Hum. Genet.
(1998)
V. Alvarez et al.
Mutational analysis of the CCR5 and CXCR4 genes (HIV-1 co-receptors) in resistance to HIV-1 infection and AIDS development among intravenous drug users
Hum. Genet.
(1998)
R.M. Barbouche et al.
Contrasting frequencies of CCR5Δ32 and CCR2-641 alleles in the Tunisian population
J. Acquired Immune Defic. Syndr.
(2001)
E. Battiloro et al.
Distribution of the CCR5Δ32 allele in Italian type 1-infected and normal individuals
AIDS Res. Hum. Retrov.
(2000)
I. Blanco et al.
Alpha-1-anti-trypsin PI phenotypes S and Z in Europe: an analysis of the published surveys
Clin. Genet.
(2001)
C. Christodoulou et al.
Low frequencies of CCR5Δ32 allele among Greeks in Cyprus
AIDS Res. Hum. Retrov.
(1997)

M. Dean et al.

Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene

Science

(1996)

E. Elharti et al.

Frequency of the CCR5Δ32 allele in the Moroccan population

AIDS Res. Hum. Retrov.

(2000)

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The CCR5Δ32 allele as an HIV infection resistance marker: Possible evolutionary theories of origin
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The CCR5Δ32 allele has been a focus of previous research in population genetics. This 32-bp deletion allele, present in heterozygous or homozygous genotype, allows for partial or complete resistance, respectively, to the R5 HIV strain infection. In a healthy human, CCR5 (CC chemokine receptor 5) functions as a part of immune system, but in those who are exposed to HIV, it also acts as a co-receptor for the viral entry into the host cell. Individuals carrying the CCR5Δ32 are not capable of forming the functional CCR5 protein and the virus therefore cannot enter the host cell. This allele is also interesting because it occurs in European populations at the frequency of 10 % for the heterozygotes and 1 % for the homozygotes, but is essentially absent in other populations, which raised the question on how and when the allele originated and how it reached the current frequency variation. The estimated age of the allele allows for a spectrum of causative agents and historical events to be considered, including the Viking raids, smallpox infection, the Black Death (bubonic plague), and hemorrhagic fevers. Although many of these theories are now regarded as incorrect, we are summarizing them in the current historical review, along with the arguments that either support or advocate against their validity, in order to offer a chronological pathway of knowledge development related to this question.
Antiretrovirals to CCR5 CRISPR/Cas9 gene editing - A paradigm shift chasing an HIV cure
2023, Clinical Immunology
The evolution of drug-resistant viral strains and anatomical and cellular reservoirs of HIV pose significant clinical challenges to antiretroviral therapy. CCR5 is a coreceptor critical for HIV host cell fusion, and a homozygous 32-bp gene deletion (∆32) leads to its loss of function. Interestingly, an allogeneic HSCT from an HIV-negative ∆32 donor to an HIV-1-infected recipient demonstrated a curative approach by rendering the recipient's blood cells resistant to viral entry. Ex vivo gene editing tools, such as CRISPR/Cas9, hold tremendous promise in generating allogeneic HSC grafts that can potentially replace allogeneic ∆32 HSCTs. Here, we review antiretroviral therapeutic challenges, clinical successes, and failures of allogeneic and allogeneic ∆32 HSCTs, and newer exciting developments within CCR5 editing using CRISPR/Cas9 in the search to cure HIV.
What is the relationship between the functional importance of a gene and its degree of polymorphism? A within- and between-species perspective
2023, Bulletin de l'Academie Nationale de Medecine
Un gène est considéré comme essentiel ou important d’un point de vue fonctionnel lorsque sa perte de fonction entraîne un phénotype morbide ou létal, selon la symptomatologie clinique chez l’homme, et/ou en fonction des conséquences d’une mutation naturelle ou d’une invalidation chez l’animal. Selon cette définition, ces gènes dits importants devraient a priori être très conservés et laisser peu de place à une variabilité génétique. Cependant, le lien entre l’importance fonctionnelle d’un gène et son degré de polymorphisme est plus complexe qu’il n’y paraît. Dans cette revue, nous montrons qu’il y a de la place pour un certain degré de variabilité pour les gènes essentiels. Tout d’abord chez l’homme, la prévalence de certaines maladies génétiques plutôt très invalidantes reste élevée car les porteurs à l’état hétérozygotes semblent être protégés de maladies infectieuses ou parasitaires. L’environnement peut également provoquer une adaptation des espèces à travers l’évolution de certains gènes, dans des séquences codantes ou non codantes. La sélection positive des gènes peut aussi jouer un rôle dans la spéciation, en particulier sur les gènes des systèmes immunitaire, reproducteur et nerveux. Enfin les séquences régulatrices des gènes jouent souvent un rôle crucial dans les différences de morphologie entre espèces et l’adaptation à l’environnement au sein des espèces.
A gene is considered essential or functionally important when its loss of function results in a morbid or lethal phenotype, depending on the clinical symptomatology in humans, and/or depending on the consequences of a natural mutation or invalidation in animals. According to this definition, these so-called important genes should a priori be highly conserved and leave little room for genetic variability. However, the link between the functional importance of a gene and its degree of polymorphism is more complex than it seems. In this review, we show that there is room for some degree of variability for essential genes. First of all, in humans, the prevalence of certain genetic diseases that are rather very debilitating remains high because carriers in the heterozygous state seem to be protected from infectious or parasitic diseases. The environment can also cause species to adapt through the evolution of certain genes, in coding or non-coding sequences. Positive gene selection may also play a role in speciation, particularly on immune, reproductive and nervous system genes. Finally, the regulatory sequences of genes often play a crucial role in differences in morphology between species and adaptation to the environment within species.
HIV cure research: Advances and prospects
2014, Virology
Citation Excerpt :
Despite the impact of HSC transplantation on reducing HIV reservoirs, this kind of treatment is not a viable option for the majority of HIV infected patients, since it is a risky and expensive procedure that is recommended only for those who develop cancer. Furthermore, CCR5 ∆32 homozygous donors are rare (1% of caucasians) (Lucotte, 2002), what makes the search for a compatible donor with the protective genotype an additional challenge. “HIV controllers” or “elite controllers” correspond to a small percentage of HIV infected patients that can naturally control viral replication below the levels of detection with standard clinical assays.
Thirty years after the identification of HIV, a cure for HIV infection is still to be achieved. Advances of combined antiretroviral therapy (cART) in recent years have transformed HIV infection into a chronic disease when treatment is available. However, in spite of the favorable outcomes provided by the newer therapies, cART is not curative and patients are at risk of developing HIV-associated disorders. Moreover, universal access to antiretroviral treatment is restricted by financial obstacles. This review discusses the most recent strategies that have been developed in the search for an HIV cure and to improve life quality of people living with HIV.
Determination of the CCR5∆32 frequency in Emiratis and Tunisians and the screening of the CCR5 gene for novel alleles in Emiratis
2013, Gene
Citation Excerpt :
Several research studies have shown that this variant was more prevalent in Caucasians and almost absent in Asians. The greatest CCR5∆32 frequency was identified particularly in North European subjects (10–20%), while the frequency declines as you go from north to south Europe reaching 1% among Balkan Peninsula (Arenzana-Seisdedos and Parmentier, 2006; Galvani and Novembre, 2005; Libert et al., 1998; Limborska et al., 2002; Lucotte, 2002). Globally, the distribution of the CCR5∆32 allele varies widely with 21.7% in North American Caucasians, 20.93% in Ashkenazi Jews, 6.9% in Hispanics, 5.8% in African-Americans, 5.3% in Colombia, 2% in North Africa, and 0.6% in Asian-Americans, (Lucotte and Smets, 2003; Su et al., 2000; Zimmerman et al., 1997).
The chemokine receptor components play crucial roles in the immune system and some of them serve as co-receptors for the HIV virus. Several studies have documented that variants in chemokine receptors are correlated with susceptibility and resistance to infection with HIV virus. For example, mutations in the chemokine receptor 5 gene (CCR5) resulting in loss-of-function (such as the homozygous CCR5∆32) confer high degree of resistance to HIV infection. Heterozygotes for these variants exhibit slow progression to AIDS. The prevalence of CCR5 polymorphisms varies among ethnic and geographical groups. For example, the CCR5∆32 variant is present in 10–15% of north Europeans but is rarely encountered among Africans. This study aims to identify the prevalence of some CCR5 variants in two geographically distant Arab populations (namely Emiratis and Tunisians).
The prevalence of CCR5 gene variants including CCR5∆32, FS299, C101X, A29S and C178R has been determined using PCR and direct DNA sequencing. A total of 403 unrelated healthy individuals (253 Emiratis and 150 Tunisians) were genotyped for the CCR5∆32 variant using PCR amplification and gel electrophoresis. In addition, 200 Emiratis have been screened for other SNPs using Sanger DNA sequencing.
Among Emiratis, the allele frequency of the CCR5∆32 variant has been found to be 0.002. In addition, two variants L55Q and A159 were found at a frequency of 0.002. Moreover, the prevalence of the CCR5∆32 variant in Tunisians was estimated to be 0.013 which is relatively higher than its frequency in Emiratis but lower than Europeans.
We conclude that the allele frequency of the most critical CCR5 polymorphism (∆32) is extremely low among Emiratis compared to other Arabs and North Europeans. In addition, very low allele frequencies of other CCR5 polymorphisms have been detected among Emiratis.
Site-specific Genome Editing in PBMCs With PLGA Nanoparticle-delivered PNAs Confers HIV-1 Resistance in Humanized Mice
2013, Molecular Therapy Nucleic Acids
Citation Excerpt :
Heterozygous PBMCs were used to allow accurate quantification of the editing frequency at a single locus. Furthermore, ~10% of all northern Europeans carry one copy of the Δ32 allele and therefore represent a potential genotype in many HIV-1–affected individuals.11 NPs were formulated to contain the fluorescent dye coumarin-6 (C6) to quantify NP uptake into human PBMCs, as C6 is not released substantially from the particles during the period of these experiments.
Biodegradable poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) encapsulating triplex-forming peptide nucleic acids (PNAs) and donor DNAs for recombination-mediated editing of the CCR5 gene were synthesized for delivery into human peripheral blood mononuclear cells (PBMCs). NPs containing the CCR5-targeting molecules efficiently entered PBMCs with low cytotoxicity. Deep sequencing revealed that a single treatment with the formulation resulted in a targeting frequency of 0.97% in the CCR5 gene and a low off-target frequency of 0.004% in the CCR2 gene, a 216-fold difference. NP-treated PBMCs efficiently engrafted immunodeficient NOD-scid IL-2rγ^-/- mice, and the targeted CCR5 modification was detected in splenic lymphocytes 4 weeks posttransplantation. After infection with an R5-tropic strain of HIV-1, humanized mice with CCR5-NP–treated PBMCs displayed significantly higher levels of CD4⁺ T cells and significantly reduced plasma viral RNA loads compared with control mice engrafted with mock-treated PBMCs. This work demonstrates the feasibility of PLGA-NP–encapsulated PNA-based gene-editing molecules for the targeted modification of CCR5 in human PBMCs as a platform for conferring HIV-1 resistance.

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Infection, Genetics and Evolution

Abstract

Introduction

Section snippets

Molecular methods used

Allelic frequencies in 40 populations

Discussion

References (25)

Homozygous defect in HIV-1 co-receptors accounts for resistance of some multiply-exposed individuals to HIV-1 infection

Cell

Frequencies of the CC chemokine receptor 5 Δ32 allele in various populations of defined racial background

Biomed. Pharmacother.

Frequency analysis and allele map in favor of the Celtic origin of the C282Y mutation of hemochromatosis

Blood Cells Mol. Dis.

Δ32 Mutation frequencies of the CCR5 co-receptor in different French regions

C. R. Acad. Sci. Paris

Dating the origin of the CCR5Δ32 AIDS-resistance allele by the coalescence of haplotypes

Am. J. Hum. Genet.

Mutational analysis of the CCR5 and CXCR4 genes (HIV-1 co-receptors) in resistance to HIV-1 infection and AIDS development among intravenous drug users

Hum. Genet.

Contrasting frequencies of CCR5Δ32 and CCR2-641 alleles in the Tunisian population

J. Acquired Immune Defic. Syndr.

Distribution of the CCR5Δ32 allele in Italian type 1-infected and normal individuals

AIDS Res. Hum. Retrov.

Alpha-1-anti-trypsin PI phenotypes S and Z in Europe: an analysis of the published surveys

Clin. Genet.

Low frequencies of CCR5Δ32 allele among Greeks in Cyprus

AIDS Res. Hum. Retrov.

Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene

Science

Frequency of the CCR5Δ32 allele in the Moroccan population

AIDS Res. Hum. Retrov.

Cited by (58)

The CCR5Δ32 allele as an HIV infection resistance marker: Possible evolutionary theories of origin

Antiretrovirals to CCR5 CRISPR/Cas9 gene editing - A paradigm shift chasing an HIV cure

What is the relationship between the functional importance of a gene and its degree of polymorphism? A within- and between-species perspective

HIV cure research: Advances and prospects

Determination of the CCR5∆32 frequency in Emiratis and Tunisians and the screening of the CCR5 gene for novel alleles in Emiratis

Site-specific Genome Editing in PBMCs With PLGA Nanoparticle-delivered PNAs Confers HIV-1 Resistance in Humanized Mice