PMID- 12374865
OWN - NLM
STAT- MEDLINE
DCOM- 20021204
LR  - 20240410
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 99
IP  - 21
DP  - 2002 Oct 15
TI  - 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.
PG  - 13795-800
AB  - 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.
FAU - Gonzalez, Enrique
AU  - Gonzalez E
AD  - Veterans Administration Research Center for AIDS and HIV-1 Infection and 
      University of Texas Health Science Center, San Antonio, TX 78229, USA.
FAU - Rovin, Brad H
AU  - Rovin BH
FAU - Sen, Luisa
AU  - Sen L
FAU - Cooke, Glen
AU  - Cooke G
FAU - Dhanda, Rahul
AU  - Dhanda R
FAU - Mummidi, Srinivas
AU  - Mummidi S
FAU - Kulkarni, Hemant
AU  - Kulkarni H
FAU - Bamshad, Michael J
AU  - Bamshad MJ
FAU - Telles, Vanessa
AU  - Telles V
FAU - Anderson, Stephanie A
AU  - Anderson SA
FAU - Walter, Elizabeth A
AU  - Walter EA
FAU - Stephan, Kevin T
AU  - Stephan KT
FAU - Deucher, Michael
AU  - Deucher M
FAU - Mangano, Andrea
AU  - Mangano A
FAU - Bologna, Rosa
AU  - Bologna R
FAU - Ahuja, Seema S
AU  - Ahuja SS
FAU - Dolan, Matthew J
AU  - Dolan MJ
FAU - Ahuja, Sunil K
AU  - Ahuja SK
LA  - eng
GR  - R37 AI046326/AI/NIAID NIH HHS/United States
GR  - P01 DK055546/DK/NIDDK NIH HHS/United States
GR  - R21 AI046326/AI/NIAID NIH HHS/United States
GR  - AI 46326/AI/NIAID NIH HHS/United States
GR  - R01 AI046326/AI/NIAID NIH HHS/United States
GR  - P01 DK 55546/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20021008
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Chemokine CCL2)
SB  - IM
MH  - AIDS Dementia Complex/*genetics/metabolism/*pathology
MH  - Adult
MH  - Alleles
MH  - Chemokine CCL2/*genetics/metabolism
MH  - Child
MH  - Cohort Studies
MH  - Genetic Variation
MH  - Genotype
MH  - HIV Infections/*genetics/metabolism/*pathology
MH  - HIV-1
MH  - Haplotypes
MH  - Humans
MH  - Monocytes/*pathology
MH  - *Mutation
MH  - Phenotype
MH  - Polymorphism, Single Nucleotide
MH  - Risk Factors
PMC - PMC129777
EDAT- 2002/10/11 04:00
MHDA- 2002/12/05 04:00
PMCR- 2003/04/15
CRDT- 2002/10/11 04:00
PHST- 2002/10/11 04:00 [pubmed]
PHST- 2002/12/05 04:00 [medline]
PHST- 2002/10/11 04:00 [entrez]
PHST- 2003/04/15 00:00 [pmc-release]
AID - 202357499 [pii]
AID - 3574 [pii]
AID - 10.1073/pnas.202357499 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13795-800. doi: 
      10.1073/pnas.202357499. Epub 2002 Oct 8.