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Multiple Products Derived from Two CCL4 Loci: High Incidence of a New Polymorphism in HIV⁺ Patients¹

Roger Colobran^*,, Patricia Adreani^*, Yaqoub Ashhab^*, Anuska Llano, José A. Esté, Orlando Dominguez^*, Ricardo Pujol-Borrell^*, and Manel Juan^2,*,

^* Laboratory of Immunobiology for Research and Application to Diagnosis, Centre for Transfusion and Tissue Bank, Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, and Retrovirology Laboratory, IrsiCaixa Foundation. Hospital Universitari Germans Trias i Pujol, Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain

Human CCL4/macrophage inflammatory protein (MIP)-1 and CCL3/MIP-1 are two highly related molecules that belong to a cluster of inflammatory CC chemokines located in chromosome 17. CCL4 and CCL3 were formed by duplication of a common ancestral gene, generating the SCYA4 and SCYA3 genes which, in turn, present a variable number of additional non-allelic copies (SCYA4L and SCYA3L1). In this study, we show that both CCL4 loci (SCYA4 and SCYA4L) are expressed and alternatively generate spliced variants lacking the second exon. In addition, we found that the SCYA4L locus is polymorphic and displays a second allelic variant (hereinafter SCYA4L2) with a nucleotide change in the intron 2 acceptor splice site compared with the one described originally (hereinafter SCYA4L1). Therefore, the pattern of SCYA4L2 transcripts is completely different from that of SCYA4L1, since SCYA4L2 uses several new acceptor splice sites and generates nine new mRNAs. Furthermore, we analyzed the contribution of each locus (SCYA4 and SCYA4L1/L2) to total CCL4 expression in human CD8 T cells by RT-amplified fragment length polymorphism and real-time PCR, and we found that L2 homozygous individuals (L2L2) only express half the levels of CCL4 compared with L1L1 individuals. The analysis of transcripts from the SCYA4L locus showed a lower level in L2 homozygous compared with L1 homozygous individuals (12% vs 52% of total CCL4 transcripts). A possible clinical relevance of these CCL4 allelic variants was suggested by the higher frequency of the L2 allele in a group of HIV⁺ individuals (n = 175) when compared with controls (n = 220, 28.6% vs 16.6% (p = 0.00016)).