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Decreased NK Cell Frequency and Function Is Associated with Increased Risk of KIR3DL Allele Polymorphism in Simian Immunodeficiency Virus-Infected Rhesus Macaques with High Viral Loads¹

Pavel Bostik^2,*, Jaruda Kobkitjaroen^*,, Weining Tang, Francois Villinger^*, Lara E. Pereira^*, Dawn M. Little^*, Susan T. Stephenson^*, Mark Bouzyk and Aftab A. Ansari^*

^* Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322; Center for Medical Genomics, Emory University, Atlanta, GA 30322; and Department of Clinical Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

NK cells have been established as an important effector of innate immunity in a variety of viral infections. In HIV-1 infection in humans, alterations of NK cell function, frequency, and expression of various NK receptors have been reported to be associated with differential dynamics of disease progression. Expression of certain alleles of KIR3DL and KIR3DS receptors on NK cells was shown to correlate with levels of virus replication. In the SIV-infected rhesus macaque (RM) model of AIDS, several families of killer inhibitory Ig-related receptors (KIR receptors) corresponding to their human counterparts have been characterized, but only at the level of individual sequence variants. Here we define 14 different alleles of KIR3DL expressed among 38 SIV-infected RM, characterized by either high or low levels of SIV replication, by analyzing multiple sequences from individual animals and show an unequal distribution of certain alleles in these cohorts. High levels of SIV replication were associated with significant increases in KIR3DL mRNA levels in addition to decreases in both the frequency and function of NK cells in these animals. The higher frequency of inheritance of two KIR3DL alleles characterized by a single nucleotide polymorphism 159 H/Q was associated with RM that exhibited high plasma viral load. This data for the first time defines multiple alleles of KIR3DL in RM and shows an association between virus control, NK cell function and genetic polymorphisms of KIR receptors.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health Grants R01 AI65362 (to P.B.), R01 AI51994 (to A.A.A.), and the Yerkes National Primate Research Center base Grant DRR000165.

² Address correspondence and reprint requests to Dr. Pavel Bostik, Department of Pathology and Laboratory Medicine, Emory University, WMB Room 2337A; 101 Woodruff Circle, Atlanta, GA 30322, E-mail address: Pavel.Bostik{at}emory.edu

³ Abbreviations used in this paper: KIR, killer inhibitory Ig-like receptor; RM, rhesus macaque; VL, viral load; HVL, high VL; LVL, low VL; SNP, single nucleotide polymorphism.

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