CCR5Δ32 Genotypes in a German HIV-1 Seroconverter Cohort and Report of HIV-1 Infection in a CCR5Δ32 Homozygous Individual

Oh, Djin-Ye; Jessen, Heiko; Kücherer, Claudia; Neumann, Konrad; Oh, Nari; Poggensee, Gabriele; Bartmeyer, Barbara; Jessen, Arne B; Pruss, Axel; Schumann, Ralf R.; Hamouda, Osamah

doi:10.1371/journal.pone.0002747

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CCR5Δ32 Genotypes in a German HIV-1 Seroconverter Cohort and Report of HIV-1 Infection in a CCR5Δ32 Homozygous Individual

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Author(s): Djin-Ye Oh ¹ ^, ^* , Heiko Jessen ² , Claudia Kücherer ³ , Konrad Neumann ⁴ , Nari Oh ² , Gabriele Poggensee ³ , Barbara Bartmeyer ³ , Arne Jessen ² , Axel Pruss ⁵ , Ralf R. Schumann ¹ , Osamah Hamouda ³

Editor(s): Srikanth Tripathy

Publication date (Electronic): 23 July 2008

Journal: PLoS ONE

Publisher: Public Library of Science

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Abstract

Background

Homozygosity (Δ32/Δ32) for the 32 bp deletion in the chemokine receptor 5 (CCR5) gene is associated with strong resistance against HIV infection. Heterozygosity is associated with protection of HIV-1 disease progression.

Methodology/Principal Findings

We genotyped a population of 737 HIV-positive adults and 463 healthy controls for the CCR5Δ32 deletion and found heterozygous frequencies of 16.2% (HIV-negative) and 17.5% (HIV-positive) among Caucasian individuals. Analysis of CCR5Δ32 influence on disease progression showed notably lower viral setpoints and a longer time to a CD4 count of <200 µl ⁻¹ in seroconverters heterozygous for the deletion. Furthermore, we identified one HIV-positive man homozygous for the Δ32 deletion.

Conclusions/Significance

The protective effect of CCR5 Δ32 heterozygosity is confimed in a large cohort of German seroconverters. The HIV-infected CCR5 Δ32 homozygous individual, however, displays extremely rapid disease progression. This is the 12th case of HIV-infection in this genotype described worldwide.

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Most cited references 43

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Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study.

M. Dean, M. Carrington, C. Winkler … (1996)

The chemokine receptor 5 (CKR5) protein serves as a secondary receptor on CD4(+) T lymphocytes for certain strains of human immunodeficiency virus-type 1 (HIV-1). The CKR5 structural gene was mapped to human chromosome 3p21, and a 32-base pair deletion allele (CKR5Delta32) was identified that is present at a frequency of approximately0.10 in the Caucasian population of the United States. An examination of 1955 patients included among six well-characterized acquired immunodeficiency syndrome (AIDS) cohort studies revealed that 17 deletion homozygotes occurred exclusively among 612 exposed HIV-1 antibody-negative individuals (2.8 percent) and not at all in 1343 HIV-1-infected individuals. The frequency of CKR5 deletion heterozygotes was significantly elevated in groups of individuals that had survived HIV-1 infection for more than 10 years, and, in some risk groups, twice as frequent as their occurrence in rapid progressors to AIDS. Survival analysis clearly shows that disease progression is slower in CKR5 deletion heterozygotes than in individuals homozygous for the normal CKR5 gene. The CKR5Delta32 deletion may act as a recessive restriction gene against HIV-1 infection and may exert a dominant phenotype of delaying progression to AIDS among infected individuals.

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HLA and HIV-1: heterozygote advantage and B35-Cw04 disadvantage.

M. Carrington, G. Nelson, M. P. Martín … (1999)

A selective advantage against infectious disease associated with increased heterozygosity at the human major histocompatibility complex [human leukocyte antigen (HLA) class I and class II] is believed to play a major role in maintaining the extraordinary allelic diversity of these genes. Maximum HLA heterozygosity of class I loci (A, B, and C) delayed acquired immunodeficiency syndrome (AIDS) onset among patients infected with human immunodeficiency virus-type 1 (HIV-1), whereas individuals who were homozygous for one or more loci progressed rapidly to AIDS and death. The HLA class I alleles B*35 and Cw*04 were consistently associated with rapid development of AIDS-defining conditions in Caucasians. The extended survival of 28 to 40 percent of HIV-1-infected Caucasian patients who avoided AIDS for ten or more years can be attributed to their being fully heterozygous at HLA class I loci, to their lacking the AIDS-associated alleles B*35 and Cw*04, or to both.

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Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1.

Maureen P. Martin, Ying Qi, Xiaojiang Gao … (2007)

Allotypes of the natural killer (NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV)+ individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data correlate very well with previously defined functional differences that distinguish KIR3DL1 allotypes. The various epistatic effects observed here for common, distinct KIR3DL1 and HLA-B Bw4 combinations are unprecedented with regard to any pair of genetic loci in human disease, and indicate that NK cells may have a critical role in the natural history of HIV infection.

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Author and article information

Contributors

: Role: Editor

Journal

Journal ID (nlm-ta): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2008

Publication date (Electronic): 23 July 2008

Volume: 3

Issue: 7

Electronic Location Identifier: e2747

Affiliations

[1 ]Institute of Microbiology and Hygiene, Charité University Medical Center, Berlin, Germany

[2 ]Gemeinschaftspraxis Jessen-Jessen-Stein, Berlin, Germany

[3 ]Robert Koch-Institute, Berlin, Germany

[4 ]Department of Medical Biometry and Clinical Epidemiology, Charité University Medical Center, Berlin, Germany

[5 ]Institute of Transfusion Medicine, Charité University Medical Center, Berlin, Germany

National AIDS Research Institute, India

Author notes

* E-mail: doh@ 123456tuftsmedicalcenter.org

Recruited patients in an HIV clinic: DO HJ NO AJ. Collected EDTA blood samples and clinical data of these patients: DO HJ NO AJ. Obtained the ethical vote for this collective: DO HJ CK NO GP BB AJ. Provided detailed clinical information on the CCR5-delta 32 homozygous individual: HJ. Provided DNA samples of the German HIV-1 Seroconverter Study patients: CK GP BB. Collected patient data: CK GP BB. Provided sequence-inferred coreceptor usage information for the CCR5-delta 32 homozygous individual: CK. Performed statistical data analysis: KN. Recruited healthy controls: AP. Designed and supervised the genotyping efforts, and wrote the manuscript: RS. Designed, supervised and conducted the German HIV-1 Seroconverter Study: OH.

[¤]

Current address: The Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts, United States of America

Article

Publisher ID: 08-PONE-RA-04665 - CORRECTION

DOI: 10.1371/journal.pone.0002747

PMC ID: 2453227

PubMed ID: 18648518

SO-VID: d9ec982c-4fdf-4866-b566-83499a366899

Copyright © Oh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 12 May 2008

Date accepted : 29 June 2008

Page count

Pages: 6

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