title: HIV-1 infection and AIDS dementia are influenced by a mutant MCP-1 allele linked to increased monocyte infiltration of tissues and MCP-1 levels.
abstract: Studies in humans and in experimental models of HIV-1 infection indicate an important role for monocyte chemoattractant protein-1 (MCP-1; also known as CC chemokine ligand 2), a potent chemoattractant and activator of mononuclear phagocytes (MP) in the pathogenesis of HIV-associated dementia (HAD). We determined the influence of genetic variation in MCP-1 on HIV-1 pathogenesis in large cohorts of HIV-1-infected adults and children. In adults, homozygosity for the MCP-1 -2578G allele was associated with a 50% reduction in the risk of acquiring HIV-1. However, once HIV-1 infection was established, this same MCP-1 genotype was associated with accelerated disease progression and a 4.5-fold increased risk of HAD. We examined the molecular and cellular basis for these genotype-phenotype associations and found that the mutant MCP-1 -2578G allele conferred greater transcriptional activity via differential DNA-protein interactions, enhanced protein production in vitro, increased serum MCP-1 levels, as well as MP infiltration into tissues. Thus, MCP-1 expression had a two-edged role in HIV-1 infection: it afforded partial protection from viral infection, but during infection, its proinflammatory properties and ability to up-regulate HIV-1 replication collectively may contribute to accelerated disease progression and increased risk of dementia. Our findings suggest that MCP-1 antagonists may be useful in HIV-1 infection, especially for HAD, and that HIV+ individuals possessing the MCP-1 -2578G allele may benefit from early initiation of antiretroviral drugs that effectively cross the blood-brain barrier. In a broader context, the MCP-1 -2578G allele may serve as a genetic determinant of outcome of other disease states in which MP-mediated tissue injury is central to disease pathogenesis.
authors.affiliation: Veterans Administration Research Center for AIDS and HIV-1 Infection and University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Enrique
authors.initials: E
authors.lastname: Gonzalez
authors.forename: Brad H
authors.initials: BH
authors.lastname: Rovin
authors.forename: Luisa
authors.initials: L
authors.lastname: Sen
authors.forename: Glen
authors.initials: G
authors.lastname: Cooke
authors.forename: Rahul
authors.initials: R
authors.lastname: Dhanda
authors.forename: Srinivas
authors.initials: S
authors.lastname: Mummidi
authors.forename: Hemant
authors.initials: H
authors.lastname: Kulkarni
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.forename: Vanessa
authors.initials: V
authors.lastname: Telles
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Anderson
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Walter
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Stephan
authors.forename: Michael
authors.initials: M
authors.lastname: Deucher
authors.forename: Andrea
authors.initials: A
authors.lastname: Mangano
authors.forename: Rosa
authors.initials: R
authors.lastname: Bologna
authors.forename: Seema S
authors.initials: SS
authors.lastname: Ahuja
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Dolan
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Ahuja
mesh_terms: D015526:AIDS Dementia Complex / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000483:Alleles; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D002648:Child; D015331:Cohort Studies; D014644:Genetic Variation; D005838:Genotype; D015658:HIV Infections / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015497:HIV-1; D006239:Haplotypes; D006801:Humans; D009000:Monocytes / Q000473:pathology*; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D018932:Chemokine CCL2