CCR5 promoter polymorphism determines macrophage CCR5 density and magnitude of HIV-1 propagation in vitro - PubMed (original) (raw)

Comparative Study

CCR5 promoter polymorphism determines macrophage CCR5 density and magnitude of HIV-1 propagation in vitro

Janelle R Salkowitz et al. Clin Immunol. 2003 Sep.

Abstract

The common CCR5 promoter polymorphism at position -2459 (A/G) has been associated with differences in the rate of progression to AIDS, where HIV-1-infected individuals with the CCR5 -2459 G/G genotype exhibit slower disease progression than those with the A/A genotype. Mechanisms underlying the relationship between these polymorphisms and disease progression are not known. Here through in vitro infection of peripheral blood mononuclear cells obtained from healthy Caucasian blood donors with macrophage-tropic HIV-1 isolates we observed low, medium, and high viral propagation in association with G/G, A/G, and A/A promoter genotypes, respectively. Flow cytometric analysis of unstimulated CD14+ monocytes from these same donors revealed a similar hierarchy of CCR5 receptor density in association with promoter genotypes. Finally, PBMC from persons with the G/G promoter polymorphism produced higher levels of beta-chemokines after in vitro stimulation. Thus, the CCR5 -2459 (A/G) promoter polymorphism determines CCR5 expression and predicts the magnitude of HIV-1 propagation in vitro. These findings may provide important insight regarding the regulation of mechanisms that influence the rate of HIV-1 propagation and progression to AIDS.

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Figures

Fig. 1

Fig. 1

CCR5 expression on CD14+ monocytes. The number of chemokine receptors/cell from 16 uninfected Caucasian blood donors is shown on the y axis. The number of G/G (△) and A/G (○) donors were 10 (4 and 6, respectively), and the number of A/A donors was 6 (□).

Fig. 2

Fig. 2

CCR5 –2459 SNP and in vitro infection with R5-tropic HIV-1 isolate JR-FL. Magnitude of HIV-1 p24 antigen produced (y axis) over time (x axis). (A) Suboptimal stimulation of PBMC obtained from four people with the G/G genotype (○) produced on average 1.2 ± 1.7 (mean ± SE) ng HIV-1 p24 antigen/ml, PBMC obtained from six people with the A/G genotype (▽) produced on average 15.7 ± 12.8 ng/p24 antigen/ml, PBMC obtained from five people with the A/A genotype (□) produced on average 109 ± 105.7 ng/ml (P < 0.05, Kruskall–Wallis test). (B) Near-optimal stimulation of PBMC from persons with the G/G genotype produced 54.3 ± 34.6 ng p24 antigen/ml; A/G PBMC produced 61 ± 40.3 ng/ml; A/A PBMC produced 131 ± 90.2 ng/ml (P < 0.7, Kruskal–Wallis test) over 11 days in culture.

Fig. 3

Fig. 3

CCR5 (–)2459 SNP and supernatant β_-chemokine production. In vitro production of β_-chemokines at near-optimal stimulation conditions: (A). MIP-1_α, (B) MIP-1_β, and (C) RANTES. The number of G/G donors was 5, A/G donors was 7, and A/A donors was 6.

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