Regulation of CCR5 and CXCR4 expression by type 1 and type 2 cytokines: CCR5 expression is downregulated by IL-10 in CD4-positive lymphocytes

HIV-1 transmission and disease progression is, in general, characterized by initial predominance of macrophage tropic, non-syncytium-inducing strains followed by a switch to T-cell tropic, syncytium-inducing strains. Using se nsitive, quantitative kinetic RT-PCR, we examined cytokine regulation of tr opism-specific HIV-1 coreceptor expression in PBMCs from HIV-1-seronegative individuals. Proinflammatory (TNF-alpha. and IL-12) and type 1 cytokines ( IFN-gamma and IL-2) significantly upregulated CCR5 (wt allele) mRNA express ion in CCR5 homozygous wild-type (wt/wt) and heterozygous individuals (wt/d el) (P < 0.02). CCR5 (wt) mRNA expression in unstimulated PBMCs was signifi cantly increased in wt/wt individuals compared to that of wt/del individual s (P < 0.01), In wt/del individuals, del CCR5 mRNA was expressed at 10-fold greater levels than wt CCR5 mRNA in unstimulated PBMCs from the same indiv idual. Flow cytometry confirmed that upregulated CCR5 mRNA following type 1 cytokine stimulation leads to increased cell surface expression of CCR5 pr otein. The type 2 cytokine IL-10 downregulated both CCR5 mRNA and protein e xpression in wt/wt and wt/del individuals. Proinflammatory, type 1, and typ e 2 cytokines significantly increased CXCR4 mRNA expression in wt/wt, wt/de l, and del/del CCR5 genotypes (P < 0.02), These results suggest that change s in the cytokine milieu influence chemokine receptor expression and may ex plain emergence of tropism-specific strains facilitating HIV transmission a nd disease progression. (C) 1999 Academic Press.