ASSOCIATION OF HLA CLASS I SUPERTYPES WITH HIV–1 DISEASE PROGRESSION IN THE CHICAGO MACS: EVIDENCE FOR FREQUENCY

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TITLE: ASSOCIATION OF HLA CLASS I SUPERTYPES WITH HIV–1 DISEASE PROGRESSION IN THE CHICAGO MACS: EVIDENCE FOR FREQUENCY–DEPENDENT SELECTION

Elizabeth Trachtenberg,¹ Bette Korber,^2,3 Cristina Sollars,¹ Elizabeth Hayes,¹ Robert Funkhouser,³ Tom Kepler,¹ Peter Hraber,³ Michael Hsu,¹ Henry Erlich,^1,4 Steven Wolinsky.⁵

¹Translational Genetic Research, Children’s Hospital Oakland Research Institute, Oakland, CA; ²Theoretical Biology, Los Alamos National Laboratory, Los Alamos, NM; ³Immunology, Santa Fe Institute, Santa Fe, NM; ⁴Human Genetics, Roche Molecular Systems, Alameda, CA; ⁵⁵Infectious Disease, Northwestern University Medical School, Chicago, IL

Using the human immunodeficiency virus type–1 (HIV–1) viral load setpoint and the slope of the CD4+ cell decline as markers for disease progression, we present population–based evidence that specific HLA class I alleles and supertypes are associated with progression to acquired immunodeficiency syndrome (AIDS). Allelic resolution of class I HLA–A, –B, –C and class II DRB1, DQB1, an DPB1 was performed using the PCR and SSOP to analyze 1,000 men (436 HIV–1 seronegatives and 564 HIV–1 seroprevalents) from the Chicago Multicenter AIDS Cohort Study (MACS) with longitudinal data spanning 18 years [1]. Our results indicate that some alleles (e.g. HLA–B*56 and *37) and supertypes (e.g. B7s and B44s) are associated with rapid progression, and others (e.g. B*57, B58 supertype) are associated with slow progression. HLA supertypes, a group of HLA–A or B alleles which share functional properties by presenting similar epitopes for T cell recognition [2], may be associated with disease progression due to cross–presentation of HIV–1 peptides. In our study, the population frequency of class I supertypes was significantly correlated with the viral set point. In addition, class I homozygosity disadvantage associated with rapid progression, as previously noted [3], is supported in this cohort although our data on viral set points indicate that homozygosity for protective alleles and supertypes (e.g. B*57, B58s) appears to be advantageous. Our data also support a rare allele advantage by frequency–dependent selection as well as heterozygous advantage in the maintenance of the extensive allelic diversity of HLA loci.

1. Phair et al. J. Aquired Immune Defic. Syndr. 5:490, 1992. 2. Sette and Sidney. Immunogenetics 50:201, 1999. 3. Carrington et al. Science 283:1748, 1999.