EPIDEMIOLOGY AND SOCIAL SCIENCE The Effect of RANTES Chemokine Genetic Variants on Early HIV-1 Plasma RNA Among African American Injection Drug Users Priya Duggal, PhD, MPH,* Cheryl A. Winkler, PhD,† Ping An, MD,† Xiao-Fang Yu, ScD, MD,‡ Homayoon Farzadegan, PhD,*‡ Stephen J. O’Brien, PhD,§ Terri H. Beaty, PhD,* and David Vlahov, PhD* k Summary: HIV-1 plasma RNA is a prognostic indicator of HIV-1, and increased levels of HIV-1 plasma RNA are associated with rapid progression to AIDS. Because chemokines and chemokine receptors are involved in the binding and entry of HIV-1, possible effects of host genetics on viral RNA levels should be visible in early infection. HIV-1 plasma RNAwas measured within 2 years of seroconversion in 198 seroincident injection drug users followed in the AIDS Link to Intravenous Experience cohort. Genetic variants were identified in the chemokine receptors (CCR2, CCR5, and CCR5 promoter) and the chemokine RANTES using TaqMan and restriction fragment length polymorphism assays. Linear regression of RANTES haplotypes on early HIV-1 plasma RNA identified individuals homozygous for the RANTES R1 haplotype as having a lower viral load by almost one- half log 10 unit compared with those bearing non-RANTES R1 haplo- types (20.43, 95% confidence interval: 20.74, 20.12). Genetic var- iants in RANTES may downregulate RANTES gene expression and increase early HIV-1 plasma RNA. Because RANTES is a critical chemokine and competitively inhibits HIV-1 by binding to its recep- tor CCR5, treatment to enhance RANTES expression may assist in delaying the progression of AIDS by decreasing the initial viral load. Key Words: chemokines, RANTES, HIV-1 plasma RNA, HIV (J Acquir Immune Defic Syndr 2005;38:584–589) C hemokines and their receptors play a critical role in HIV-1 binding and entry. Chemokine receptors function as viral coreceptors with CD4 to permit binding and entry of HIV-1 into macrophage and T cells. The principal chemokine recep- tors in HIV-1 transmission and progression are CCR5 for the R5 (macrophage tropic) and CXCR4 for the X4 (T-cell tropic) viruses. Other chemokine receptors, including CCR2, may act as secondary coreceptors. 1 The chemokine RANTES is one of 3 natural ligands for CCR5. Chemokines interfere with the spread of HIV-1 by 2 mechanisms: by competitively binding to their respective re- ceptors, they block binding of HIV envelope glycoprotein, gp120, and by inducing internalization of the bound receptor, thereby reducing coreceptor availability. 2 Studies have shown a decline in RANTES levels with HIV disease progression 3 and increased production of b-chemokines, including RANTES, among HIV-exposed uninfected individuals. 4–7 Genetic epidemiologic cohort studies have shown that polymorphisms in the genes encoding these chemokines and chemokine receptors are associated with altered rates of dis- ease progression after HIV-1 infection. Genetic variants of CCR2, CCR5, and its ligand, RANTES, have been associated with both delayed disease progression (CCR5-D32, CCR2-64I, and RANTES 2403A) and accelerated disease progression (RANTES In1.C and CCR5-P1). 8–16 Although this epidemiologic evidence has aided our understanding of the importance of chemokines and chemo- kine receptors in HIV-1 disease progression, the effect of RANTES variant alleles on HIV-1 RNA levels has not been demonstrated. Clinical studies of the CCR5 genotypes have shown decreased early HIV-1 plasma RNA for individuals heterozygous for CCR5-D32. 17–19 The underlying mechanism of the 2- to 4-year delay in progression to AIDS-defining conditions afforded by CCR5-D32 in heterozygotes may result from a decrease in available CCR5. The CCR5-P1 promoter haplotype has been associated with accelerated progression to AIDS in both European and African Americans. 8,20 Unlike CCR5D32, which is rare or absent in non-Europeans, CCR5-P1 is quite frequent in all tested populations (frequency between 10% and 35%). 20,21 In African Americans, the effect of CCR5-P1 is codominant, suggesting that the CCR5 promoter haplotypes differentially regulate transcription levels of CCR5. A single nucleotide Received for publication February 11, 2004; accepted May 24, 2004. From the *Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; †Basic Research Program, Science Applications International Corporation (SAIC) Frederick, National Cancer Institute, Frederick, MD; ‡Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; §Laboratory of Genomic Diversity, National Cancer Institute, Frederick, MD; and k Center for Urban Epidemiologic Studies, New York Academy of Medicine, New York, NY. Funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400 and by the National Institute of Drug Abuse, grant DA 04334. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Reprints: David Vlahov, Center for Urban Epidemiologic Studies, The New York Academy of Medicine, 1216 Fifth Avenue, New York, NY 10029–5293 (e-mail: dvlahov@nyam.org). Copyright Ó 2005 by Lippincott Williams & Wilkins 584 J Acquir Immune Defic Syndr  Volume 38, Number 5, April 15 2005