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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.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2002 Oct 15; Vol. 99 (21), pp. 13795-800. Date of Electronic Publication: 2002 Oct 08. - Publication Year :
- 2002
-
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.
- Subjects :
- AIDS Dementia Complex metabolism
Adult
Alleles
Chemokine CCL2 metabolism
Child
Cohort Studies
Genetic Variation
Genotype
HIV Infections metabolism
HIV-1
Haplotypes
Humans
Phenotype
Polymorphism, Single Nucleotide
Risk Factors
AIDS Dementia Complex genetics
AIDS Dementia Complex pathology
Chemokine CCL2 genetics
HIV Infections genetics
HIV Infections pathology
Monocytes pathology
Mutation
Subjects
Details
- Language :
- English
- ISSN :
- 0027-8424
- Volume :
- 99
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 12374865
- Full Text :
- https://doi.org/10.1073/pnas.202357499