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Journal of Virology, September 2005, p. 11677-11684, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.11677-11684.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Combined Effect of CCR5-{Delta}32 Heterozygosity and the CCR5 Promoter Polymorphism –2459 A/G on CCR5 Expression and Resistance to Human Immunodeficiency Virus Type 1 Transmission

Florian Hladik,1,{dagger} Huanliang Liu,2,{dagger},{ddagger} Emily Speelmon,1 Devon Livingston-Rosanoff,1 Sean Wilson,1 Polachai Sakchalathorn,1 Yon Hwangbo,2 Benjamin Greene,2 Tuofu Zhu,2,3 and M. Juliana McElrath1,2,4*

Program in Infectious Diseases, Clinical Research Division, Fred Hutchinson Cancer Research Center, and Departments of,1 Laboratory Medicine,2 Microbiology,3 Medicine, University of Washington School of Medicine, Seattle, Washington4

Received 17 March 2005/ Accepted 22 June 2005

Exposed seronegative individuals (ES) with persistent high-risk sexual behavior may be less susceptible to human immunodeficiency virus type 1 (HIV-1) infection because they carry the chemokine receptor (CR) gene alleles CCR5 open reading frame (ORF) {Delta}32, CCR5 promoter –2459G, or CCR2 ORF 64I (CCR2-64I), all of which have been found to diminish HIV-1 infectivity and/or disease progression. To investigate this, we determined the haplotypes for these three genetic loci in 93 ES and 247 low-risk control individuals. To test if protective haplotypes exert their effect by modulating CR expression, we measured the protein expression of CCR5 and CXCR4 on circulating CD4+ T cells and CD14+ monocytes in 71 ES and 92 controls. To avoid investigator bias, the analysis was performed without knowledge of each subject's risk and genotype. The CCR5 –2459G allele was significantly enriched in ES Caucasian men, who constituted the majority (84%) of the ES cohort, compared to the control Caucasian men (P = 0.02). This increase was mostly attributable to a higher frequency of the –2459 A/G versus the –2459 A/A genotype in individuals heterozygous for the {Delta}32 allele (P = 0.012). No protective influence of the CCR2-64I allele was observed. The haplotypes CCR5 ORF {Delta}32/CCR5 –2459A (in complete linkage disequilibrium) and CCR5 ORF wt/CCR5 –2459G had a cumulative negative effect on the expression of CCR5, since we measured significantly reduced CCR5 densities on both T-helper cells and monocytes only when both haplotypes were present. Densities of CCR5 on lymphocytes and monocytes were correlated (r = 0.59; P < 0.0001), indicating concordance of CCR5 expression patterns across different cell types. We conclude that the CCR5 ORF {Delta}32/wt-CCR5 –2459 A/G genotype combination offers an advantage in resisting sexual HIV-1 transmission and that this effect is mediated by a relative paucity of CCR5 on potential target cells of HIV-1.

* Corresponding author. Mailing address: Fred Hutchinson Cancer Research Center, Program in Infectious Diseases, 1100 Fairview Ave. N., P.O. Box 19024, D3-100, Seattle, WA 98109-1024. Phone: (206) 667-6704. Fax: (206) 667-4411. E-mail: kd{at}u.washington.edu.

{dagger} F.H. and H.L. contributed equally to this work.

{ddagger} Present address: Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136.

Journal of Virology, September 2005, p. 11677-11684, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.11677-11684.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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