Prevalence of  CCR5delta32  in Northeastern Iran

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Abstract

Background

A 32-base pair deletion ( ∆32) in the open reading frame (ORF) of C-C motif chemokine receptor 5 (CCR5) seems to be a protective variant against immune system diseases, especially human immunodeficiency virus type 1 (HIV-1). We aimed to assess the frequency of CCR5∆32 in the healthy Iranian population.

Methods

In this study, 400 normal samples from Khorasan, northeastern Iran, were randomly selected. The frequency of CCR5∆32 carriers was investigated using PCR analysis. Allele prevalence and the fit to the Hardy-Weinberg equilibrium were analyzed.

Results

The prevalence of CCR5∆32 in the northeastern population of Iran was 0.016. Four hundred samples were studied, among which one with CCR5 ^∆32/∆32 and 11 with CCR5 ^Wild/∆32 genotype were detected.

Conclusion

This study was the first investigation for an assessment of the prevalence of CCR5∆32 in northeastern Iran. The low prevalence of CCR5∆32 allele in the Iranian population may result in the increased susceptibility to HIV-1. In addition, this prevalence is the same as that of reported in East Asia, while is lower than that in the Europeans.

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Most cited references 68

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Seamless modification of wild-type induced pluripotent stem cells to the natural CCR5Δ32 mutation confers resistance to HIV infection.

Lin Ye, Jiaming Wang, Ashley I. Beyer … (2014)

Individuals homozygous for the C-C chemokine receptor type 5 gene with 32-bp deletions (CCR5Δ32) are resistant to HIV-1 infection. In this study, we generated induced pluripotent stem cells (iPSCs) homozygous for the naturally occurring CCR5Δ32 mutation through genome editing of wild-type iPSCs using a combination of transcription activator-like effector nucleases (TALENs) or RNA-guided clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 together with the piggyBac technology. Remarkably, TALENs or CRISPR-Cas9-mediated double-strand DNA breaks resulted in up to 100% targeting of the colonies on one allele of which biallelic targeting occurred at an average of 14% with TALENs and 33% with CRISPR. Excision of the piggyBac using transposase seamlessly reproduced exactly the naturally occurring CCR5Δ32 mutation without detectable exogenous sequences. We differentiated these modified iPSCs into monocytes/macrophages and demonstrated their resistance to HIV-1 challenge. We propose that this strategy may provide an approach toward a functional cure of HIV-1 infection.

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CCR5 Levels and Expression Pattern Correlate with Infectability by Macrophage-tropic HIV-1, In Vitro

Lijun Wu, William A Paxton, Nasim Kassam … (1997)

Chemokine receptors serve as coreceptors for HIV entry into CD4+ cells. Their expression is thought to determine the tropism of viral strains for different cell types, and also to influence susceptibility to infection and rates of disease progression. Of the chemokine receptors, CCR5 is the most important for viral transmission, since CCR5 is the principal receptor for primary, macrophage-tropic viruses, and individuals homozygous for a defective CCR5 allele (Δ32/ Δ32) are highly resistant to infection with HIV-1. In this study, CCR5-specific mAbs were generated using transfectants expressing high levels of CCR5. The specificity of these mAbs was confirmed using a broad panel of chemokine receptor transfectants, and by their non-reactivity with T cells from Δ32/Δ32 individuals. CCR5 showed a distinct pattern of expression, being abundant on long-term activated, IL-2–stimulated T cells, on a subset of effector/memory T cells in blood, and on tissue macrophages. A comparison of normal and CCR5 Δ32 heterozygotes revealed markedly reduced expression of CCR5 on T cells from the heterozygotes. There was considerable individual to individual variability in the expression of CCR5 on blood T cells, that related to factors other than CCR5 genotype. Low expression of CCR5 correlated with the reduced infectability of T cells with macrophage-tropic HIV-1, in vitro. Anti-CCR5 mAbs inhibited the infection of PBMC by macrophage-tropic HIV-1 in vitro, but did not inhibit infection by T cell–tropic virus. Anti-CCR5 mAbs were poor inhibitors of chemokine binding, indicating that HIV-1 and ligands bind to separate, but overlapping regions of CCR5. These results illustrate many of the important biological features of CCR5, and demonstrate the feasibility of blocking macrophage-tropic HIV-1 entry into cells with an anti-CCR5 reagent.

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Global distribution of the CCR5 gene 32-basepair deletion.

Andrew J Clegg, Albert Liu, J Martinson … (1997)

A mutant allele of the beta-chemokine receptor gene CCR5 bearing a 32-basepair (bp) deletion (denoted delta ccr5) which prevents cell invasion by the primary transmitting strain of HIV-1 has recently been characterized. Homozygotes for the mutation are resistant to infection, even after repeated high-risk exposures, but this resistance appears not to be total, as isolated cases of HIV-positive deletion homozygotes are now emerging. The consequence of the heterozygous state is not clear, but it may delay the progression to AIDS in infected individuals. A gene frequency of approximately 10% was found for delta ccr5 in populations of European descent, but no mutant alleles were reported in indigenous non-European populations. As the total number of non-European samples surveyed was small in comparison with the Europeans the global distribution of this mutation is far from clear. We have devised a rapid PCR assay for delta ccr5 and used it to screen 3,342 individuals from a globally-distributed range of populations. We find that delta ccr5 is not confined to people of European descent but is found at frequencies of 2-5% throughout Europe, the Middle East and the Indian subcontinent (Fig. 1). Isolated occurrences are seen elsewhere throughout the world, but these most likely represent recent European gene flow into the indigenous populations. The inter-population differences in delta ccr5 frequency may influence the pattern of HIV transmission and so will need to be incorporated into future predictions of HIV levels.

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Author and article information

Contributors

Amir Tajbakhsh: Tajbakhsha921@mums.ac.ir

Mostafa Fazeli: FazeliM921@mums.ac.ir

Mehdi Rezaee: RezaeiM911@mums.ac.ir

Faezeh Ghasemi: ghasemifaezeh2015@gmail.com

Mastoureh Momen Heravi: MomenHM1@mums.ac.ir

Aida Gholoobi: GholoobiA1@mums.ac.ir

Zahra Meshkat:

ORCID: http://orcid.org/0000-0002-4032-7599

+98-51- 38012453 , meshkatz@mums.ac.ir

Journal

Journal ID (nlm-ta): BMC Med Genet

Journal ID (iso-abbrev): BMC Med. Genet

Title: BMC Medical Genetics

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2350

Publication date (Electronic): 15 November 2019

Publication date PMC-release: 15 November 2019

Publication date Collection: 2019

Volume: 20

Electronic Location Identifier: 184

Affiliations

[1 ]ISNI 0000 0001 2198 6209, GRID grid.411583.a, Department of Modern Sciences & Technologies, Faculty of Medicine, , Mashhad University of Medical Sciences, ; Mashhad, Iran

[2 ]ISNI 0000 0000 8819 4698, GRID grid.412571.4, Pharmaceutical Sciences Research Center, , Shiraz University of Medical Sciences, ; Shiraz, Iran

[3 ]ISNI 0000 0001 2198 6209, GRID grid.411583.a, Student Research Committee, Faculty of Medicine, , Mashhad University of Medical Sciences, ; Mashhad, Iran

[4 ]ISNI 0000 0001 2198 6209, GRID grid.411583.a, Department of Medical Biotechnology, School of Medicine, , Mashhad University of Medical Sciences, ; Mashhad, Iran

[5 ]GRID grid.418552.f, Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, ; Tehran, Iran

[6 ]ISNI 0000 0001 2198 6209, GRID grid.411583.a, Antimicrobial Resistance Research Center, , Mashhad University of Medical Sciences, ; P.O Box: 9196773117, Mashhad, IR Iran

Author information

Zahra Meshkat http://orcid.org/0000-0002-4032-7599

Article

Publisher ID: 913

DOI: 10.1186/s12881-019-0913-9

PMC ID: 6858674

PubMed ID: 31730458

SO-VID: 683d18d5-937c-4ea7-8feb-17c364cc817e

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 13 June 2019

Date accepted : 25 October 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100004748, Mashhad University of Medical Sciences;

Award ID: 930623

Award Recipient : Zahra Meshkat

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: hiv-1,cc chemokine receptor type 5 (ccr5),epidemiology,geographic spread,rare alleles

Data availability:

ScienceOpen disciplines: Genetics

Keywords: hiv-1, cc chemokine receptor type 5 (ccr5), epidemiology, geographic spread, rare alleles

Prevalence of CCR5delta32 in Northeastern Iran

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Decoding Infection and Transmission

Most cited references 68

Seamless modification of wild-type induced pluripotent stem cells to the natural CCR5Δ32 mutation confers resistance to HIV infection.

CCR5 Levels and Expression Pattern Correlate with Infectability by Macrophage-tropic HIV-1, In Vitro

Global distribution of the CCR5 gene 32-basepair deletion.

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