Genetic analyses of cis-acting sequences controlling expression of human immunodeficiency virus type 1 coreceptor-CCR5 gene in rabbits and CXCR4 gene in monkeys

Introduction: Human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus all use chemokine receptors (CCR5, CXCR4, and minor receptors) to gain entry into a susceptible cell and establish infection successfully by way of membrane fusion. Many such chemokine receptors that can act as entry cofactors under in vitro conditions have been identified, but the roles of CCR5 and CXCR4 chemokine receptors in infection, tropism, and pathogenesis have been studied in greater detail. The promoter region of CCR5 gene is quite polymorphic in humans, and mutations that affect the progression of HIV-1 have been identified. Study Design/Methods: We studied the nature of mutations in the CCR5 promoter region in rabbits. Large number of mutations, deletions, substitutions, and point mutations were observed all along the 400 base pair region of the promoter. Results: We show that rabbit CCR5 promoter possesses features common to both humans and monkeys and lacks the second highly polymorphic region B in the CCR5 promoter that was previously identified in monkeys. Besides providing important evolutionary information, our findings can directly make an impact on the known expression levels of CCR5 protein that can modulate the progression of HIV-1 in rabbits. The CXCR4 promoter of monkeys showed polymorphisms that were largely caused by single nucleotide changes when compared with humans. Conclusions: This distinctly different evolutionary pattern suggests a more important role for chemokine receptor-CCR5 in the host defense.