HIV-1 infection and AIDS dementia are influenced by a mutantMCP-1allele linked to increased monocyte infiltration of tissues and MCP-1 levels
| Autor: | Elizabeth A. Walter, Enrique Gonzalez, Kevin T. Stephan, Brad H. Rovin, Seema S. Ahuja, Matthew J. Dolan, Sunil K. Ahuja, Michael F. Deucher, Srinivas Mummidi, Luisa Sen, Hemant Kulkarni, Rosa Bologna, Rahul Dhanda, Stephanie A. Anderson, Andrea Mangano, Glen E. Cooke, Michael J. Bamshad, Vanessa Telles |
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| Rok vydání: | 2002 |
| Předmět: |
Adult
Chemokine AIDS Dementia Complex Genotype HIV Infections Disease Biology Polymorphism Single Nucleotide Monocytes Proinflammatory cytokine Cohort Studies Pathogenesis Risk Factors medicine Humans Dementia Allele Child Alleles Chemokine CCL2 Multidisciplinary Monocyte Genetic Variation Biological Sciences medicine.disease Phenotype medicine.anatomical_structure Haplotypes Mutation Immunology HIV-1 biology.protein |
| Zdroj: | Proceedings of the National Academy of Sciences. 99:13795-13800 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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 inMCP-1on HIV-1 pathogenesis in large cohorts of HIV-1-infected adults and children. In adults, homozygosity for theMCP-1–2578G allele was associated with a 50% reduction in the risk of acquiring HIV-1. However, once HIV-1 infection was established, this sameMCP-1genotype 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 mutantMCP-1–2578G allele conferred greater transcriptional activity via differential DNA–protein interactions, enhanced protein productionin 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 theMCP-1–2578G allele may benefit from early initiation of antiretroviral drugs that effectively cross the blood–brain barrier. In a broader context, theMCP-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. |
| Databáze: | OpenAIRE |
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