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Published online on October 8, 2002, 10.1073/pnas.202357499
PNAS | October 15, 2002 | vol. 99 | no. 21 | 13795-13800


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From the Cover
Medical Sciences
 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

(chemokine|genotype|leukocyte)

Enrique Gonzalez*,dagger , Brad H. Rovindagger ,Dagger , Luisa Sendagger ,§, Glen Cookedagger ,, Rahul Dhandadagger ,||, Srinivas Mummidi*, Hemant Kulkarni*, Michael J. Bamshad**, Vanessa Telles*, Stephanie A. Andersondagger dagger , Elizabeth A. WalterDagger Dagger , Kevin T. StephanDagger Dagger , Michael Deucher, Andrea Mangano§, Rosa Bologna§§, Seema S. Ahuja*, Matthew J. DolanDagger Dagger ,¶¶, and Sunil K. Ahuja*,¶¶

* Veterans Administration Research Center for AIDS and HIV-1 Infection and University of Texas Health Science Center, San Antonio, TX 78229; Divisions of Dagger  Nephrology and  Cardiology, Ohio State University, Columbus, OH 43210; § Laboratorio de Biología Celular y Retrovirus and §§ Servicio de Infectología, Hospital de Pediatría "J. P. Garrahan," Combate de Los Pozos 1881 (1245), Buenos Aires, Argentina; || Forest Laboratories, New York, NY 10022; ** Department of Pediatrics, University of Utah, Salt Lake City, UT 84112; and dagger dagger  Henry M. Jackson Foundation and Dagger Dagger  Infectious Diseases Service, Wilford Hall Medical Center, Lackland AFB, TX 78236

Edited by John M. Coffin, Tufts University School of Medicine, Boston, MA, and approved August 7, 2002 (received for review June 14, 2002)

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.

dagger E.G., B.H.R., L.S., G.C., and R.D. contributed equally to this work.

¶¶ To whom correspondence may be addressed. E-mail: ahujas{at}uthscsa.edu or matthew.dolan{at}59mdw.whmc.af.mil.

www.pnas.org/cgi/doi/10.1073/pnas.202357499
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