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Mother-to-Child Transmission of HIV-1: Strong Association With Certain Maternal HLA-B Alleles Independent of Viral Load Implicates Innate Immune Mechanisms

Winchester, Robert MD*; Pitt, Jane MD*; Charurat, Manhattan PhD; Magder, Laurence S. PhD, MPH; Göring, Harald H. H. MPH, MA, PhD; Landay, Alan PhD§; Read, Jennifer S. MD; Shearer, William MD, PhD**; Handelsman, Edward MD††; Luzuriaga, Katherine MD‡‡; Hillyer, George V. PhD§§; Blattner, William MD

JAIDS Journal of Acquired Immune Deficiency Syndromes: June 1st, 2004 - Volume 36 - Issue 2 - p 659-670
Basic Science

The transmission of HIV-1 from mother to child during pregnancy is unlike other types of HIV-1 transmission because the child shares major histocompatibility complex (MHC) genes with the mother during a time while the mother is induced to tolerate the paternally derived fetal MHC molecules, in part through natural killer (NK) recognition of MHC polymorphisms. The relevance of these immune mechanisms to HIV-1 transmission was assessed by determining the HLA-B alleles of mother and infant. Almost half (48%) of mothers who transmitted with low viral loads had HLA-B*1302, B*3501, B*3503, B*4402, or B*5001 alleles, compared with 8% of nontransmitting mothers (P = 0.001). Conversely, 25% of mothers who did not transmit despite high viral loads had B*4901 and B*5301, vs. 5% of transmitting mothers (P = 0.003), a pattern of allelic involvement distinct from that influencing HIV-1 infection outcome. The infant's HLA-B alleles did not appear associated with transmission risk. The HLA-B*4901 and B*5301 alleles that were protective in the mother both differed respectively from the otherwise identical susceptibility alleles, B*5001 and B*3501, by 5 amino acids encoding the ligand for the KIR3DL1 NK receptor. These results suggest that the probable molecular basis of the observed association involves definition of the maternal NK recognition repertoire by engagement of NK receptors with polymorphic ligands encoded by maternal HLA-B alleles, and that the placenta is the likely site of the effect that appears to protect against transmission of maternal HIV-1 through interrelating adaptive and innate immune recognition.

From *Columbia University, Departments of Pediatrics, Pathology and Medicine, New York, NY; †Department of Epidemiology and Preventative Medicine, Institute of Human Virology, University of Maryland, Baltimore, MD; ‡Genetics Department, Southwest Foundation for Biomedical Research, San Antonio, TX; §Department of Immunology/Microbiology, Rush Medical College, Chicago, IL; ¶Adolescent and Maternal AIDS Branch, National Institute of Child Health and Human Development, Bethesda, MD; **Department of Pediatrics, Baylor College of Medicine, Houston, TX; ††SUNY Downstate, Brooklyn, NY; ‡‡Departments of Pediatrics/Molecular Medicine, University of Massachusetts Medical School, Worcester, MA; and §§Department of Pathology and Laboratory Medicine, University of Puerto Rico School of Medicine, San Juan.

Received for publication August 26, 2003; accepted February 26, 2004.

Supported by NIH R01 AI39369. Additional support has been provided by local Clinical Research Centers as follows: Baylor College of Medicine, Houston, TX; NIH GCRC RR00188; Columbia University, New York, NY; NIH GCRC RR00645.

Jane Pitt is deceased, and this paper is dedicated to her.

Reprints: Robert Winchester, Columbia University, 30 W. 168th Street, New York, NY 10032 (e-mail: rjw8@columbia.edu).

© 2004 Lippincott Williams & Wilkins, Inc.