HLA and HIV-1: Heterozygote advantage and B*35-Cw*04 disadvantage

Science

Volumn 283, Issue 5408, 1999, Pages 1748-1752

  Carrington, Mary ^a   Nelson, George W ^a   Martin, Maureen P ^a   Kissner, Teri ^a   Vlahov, David ^b   Goedert, James J ^c   Kaslow, Richard ^d   Buchbinder, Susan ^e   Hoots, Keith ^f   O'Brien, Stephen J ^g  

^a SAIC FREDERICK INC   (United States)

^b JOHNS HOPKINS BLOOMBERG SCHOOL OF PUBLIC HEALTH   (United States)

^c Division of Cancer Epidemiology and Genetics   (United States)

^d UNIVERSITY OF ALABAMA AT BIRMINGHAM   (United States)

^e San Francisco City Clinic Cohort   (United States)

^f UNIVERSITY OF TEXAS MEDICAL SCHOOL   (United States)

^g NATIONAL CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DNA; HLA A ANTIGEN; HLA ANTIGEN CLASS 1; HLA ANTIGEN CLASS 2; HLA B ANTIGEN; HLA B35 ANTIGEN; HLA C ANTIGEN;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; ALLELE; ARTICLE; CAUCASIAN; CONTROLLED STUDY; DISEASE COURSE; GENE LOCUS; GENETIC LINKAGE; HETEROZYGOSITY; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; LYMPHOCYTE COUNT; MAJOR CLINICAL STUDY; PRIORITY JOURNAL; SEROCONVERSION; SURVIVAL RATE;

ACQUIRED IMMUNODEFICIENCY SYNDROME; ADULT; ALLELES; ANTIGEN PRESENTATION; COHORT STUDIES; DISEASE PROGRESSION; ETHNIC GROUPS; GENES, MHC CLASS I; GENETIC PREDISPOSITION TO DISEASE; HETEROZYGOTE; HIV INFECTIONS; HIV LONG-TERM SURVIVORS; HIV-1; HLA ANTIGENS; HLA-B ANTIGENS; HLA-C ANTIGENS; HOMOZYGOTE; HUMANS; KILLER CELLS, NATURAL; LOSS OF HETEROZYGOSITY; PROPORTIONAL HAZARDS MODELS; RISK;

EID: 0033548497     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.283.5408.1748     Document Type: Article

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79. For HLA class I typing, genomic DNA was isolated from patients' lymphoblastoid B cell lines or from peripheral blood lymphocytes and amplified with a panel of 96 sequence specific primers (SSP-PCR) for HLA-A, -B, and -C [M. Bunce et al., Tissue Antigens 46, 355 (1995)]. Each reaction included positive control primers that amplify a 796-base pair fragment from the third intron of HLA-DRB1. HLA class I polymerase chain reaction (PCR) products were electrophoresed in 1.5% agarose gels containing ethidium bromide, and predicted size products were visualized under ultraviolet light. To resolve cryptic (to SSP technology) heterozygosity, all homozygotes were sequenced with the ABI Big Dye terminator cycle sequencing ready reaction kit. (Applied Biosystems Division/Perkin-Elmer, Foster City, CA). Primers in the first and third introns of HLA-A, -B, and -C [N. Cereb et al., ibid. 45, 1 (1995)] were used for locus-specific amplification of exons 2 and 3. The amplified product was purified in a Microcon-100 microconcentrator column (Amicon, Beverly, MA), subjected to cycle sequencing in both orientations, according to the manufacturer's protocol, followed by isopropanol precipitation. The samples were then run on an ABI 377 sequencer (Applied Biosystems Division/Perkin-Elmer), and the sequences were analyzed with the Match Tools and MT navigator allele identification software (Applied Biosystems Division/Perkin-Elmer). Sequence analysis of 125 homozygotes for class I loci revealed 17 individuals that were heterozygous for recognized nucleotide polymorphism subtypes within the type indicated by SSP typing. Sixteen of these were heterozygous at adjacent class I loci. Only homozygotes verified by sequence analysis were considered homozygous for all analyses in this report. Each reaction included positive control primers that amplify a 796-base pair fragment from the third intron of HLA-DRB1. HLA class I polymerase chain reaction (PCR) products were electrophoresed in 1.5% agarose gels containing ethidium bromide, and predicted size products were visualized under ultraviolet light. To resolve cryptic (to SSP technology) heterozygosity, all homozygotes were sequenced with the ABI Big Dye terminator cycle sequencing ready reaction kit. (Applied Biosystems Division/Perkin-Elmer, Foster City, CA). Primers in the first and third introns of HLA-A, -B, and -C [N. Cereb et al., ibid. 45, 1 (1995)] were used for locus-specific amplification of exons 2 and 3. The amplified product was purified in a Microcon-100 microconcentrator column (Amicon, Beverly, MA), subjected to cycle sequencing in both orientations, according to the manufacturer's protocol, followed by isopropanol precipitation. The samples were then run on an ABI 377 sequencer (Applied Biosystems Division/Perkin-Elmer), and the sequences were analyzed with the Match Tools and MT navigator allele identification software (Applied Biosystems Division/Perkin-Elmer). Sequence analysis of 125 homozygotes for class I loci revealed 17 individuals that were heterozygous for recognized nucleotide polymorphism subtypes within the type indicated by SSP typing. Sixteen of these were heterozygous at adjacent class I loci. Only homozygotes verified by sequence analysis were considered homozygous for all analyses in this report.
80. For HLA class I typing, genomic DNA was isolated from patients' lymphoblastoid B cell lines or from peripheral blood lymphocytes and amplified with a panel of 96 sequence specific primers (SSP-PCR) for HLA-A, -B, and -C [M. Bunce et al., Tissue Antigens 46, 355 (1995)]. Each reaction included positive control primers that amplify a 796-base pair fragment from the third intron of HLA-DRB1. HLA class I polymerase chain reaction (PCR) products were electrophoresed in 1.5% agarose gels containing ethidium bromide, and predicted size products were visualized under ultraviolet light. To resolve cryptic (to SSP technology) heterozygosity, all homozygotes were sequenced with the ABI Big Dye terminator cycle sequencing ready reaction kit. (Applied Biosystems Division/Perkin-Elmer, Foster City, CA). Primers in the first and third introns of HLA-A, -B, and -C [N. Cereb et al., ibid. 45, 1 (1995)] were used for locus-specific amplification of exons 2 and 3. The amplified product was purified in a Microcon-100 microconcentrator column (Amicon, Beverly, MA), subjected to cycle sequencing in both orientations, according to the manufacturer's protocol, followed by isopropanol precipitation. The samples were then run on an ABI 377 sequencer (Applied Biosystems Division/Perkin-Elmer), and the sequences were analyzed with the Match Tools and MT navigator allele identification software (Applied Biosystems Division/Perkin-Elmer). Sequence analysis of 125 homozygotes for class I loci revealed 17 individuals that were heterozygous for recognized nucleotide polymorphism subtypes within the type indicated by SSP typing. Sixteen of these were heterozygous at adjacent class I loci. Only homozygotes verified by sequence analysis were considered homozygous for all analyses in this report. Each reaction included positive control primers that amplify a 796-base pair fragment from the third intron of HLA-DRB1. HLA class I polymerase chain reaction (PCR) products were electrophoresed in 1.5% agarose gels containing ethidium bromide, and predicted size products were visualized under ultraviolet light. To resolve cryptic (to SSP technology) heterozygosity, all homozygotes were sequenced with the ABI Big Dye terminator cycle sequencing ready reaction kit. (Applied Biosystems Division/Perkin-Elmer, Foster City, CA). Primers in the first and third introns of HLA-A, -B, and -C [N. Cereb et al., ibid. 45, 1 (1995)] were used for locus-specific amplification of exons 2 and 3. The amplified product was purified in a Microcon-100 microconcentrator column (Amicon, Beverly, MA), subjected to cycle sequencing in both orientations, according to the manufacturer's protocol, followed by isopropanol precipitation. The samples were then run on an ABI 377 sequencer (Applied Biosystems Division/Perkin-Elmer), and the sequences were analyzed with the Match Tools and MT navigator allele identification software (Applied Biosystems Division/Perkin-Elmer). Sequence analysis of 125 homozygotes for class I loci revealed 17 individuals that were heterozygous for recognized nucleotide polymorphism subtypes within the type indicated by SSP typing. Sixteen of these were heterozygous at adjacent class I loci. Only homozygotes verified by sequence analysis were considered homozygous for all analyses in this report.
81. The class I alleles B*35 and Cw*04 were used as a covariable in the association analysis of homozygosity (Fig. 1 and Table 1), and homozygosity was used as a covariable in the analysis of allele association with progression to AIDS (Fig. 1 and Tables 1 and 3).
82. We would like to thank D. Marti, M. McNally, M. Weedon, and L. Main for technical assistance and M. Dean, M. Smith, and C. Winkler for discussions and critical review of the manuscript. The project was funded in part with Federal funds from the National Cancer Institute, NIH, under contract number N01-CO-56000.