Associations of human leukocyte antigen DRB with resistance or susceptibility to HIV-1 infection in the Pumwani Sex Worker Cohort
ABSTRACT A group of commercial sex workers in the Pumwani Sex Worker Cohort, established in 1985 in Nairobi, Kenya, remain HIV-1 uninfected despite heavy exposure to HIV-1 through active sex work. Previous studies showed that this resistance is associated with a strong CD4+ T-cell response, which suggested that human leukocyte antigen class II antigens are important in resistance/susceptibility to HIV-1 infection. DRB1 is the most polymorphic locus among class II genes and forms haplotypes with DRB3, DRB4 and DRB5. The aim of this study is to investigate the role of DRB alleles/haplotypes on resistance/susceptibility to HIV-1 infection.
In total, 1090 women enrolled in the Pumwani cohort were genotyped for DRB1, DRB3, DRB4 and DRB5 using a high-resolution sequence-based method. Allele/haplotype frequencies were compared between HIV-positive women and women who have remained HIV negative for more than 3 years despite frequent exposure.
Human leukocyte antigen DRB genes were amplified, sequenced and genotyped using a two-step sequence-based method. Allele/haplotype frequencies were determined using PyPop32-0.6.0. Statistical analysis was conducted using SPSS 11.0 for Windows.
Three DRB1 alleles were associated with resistance: DRB1*010101 (P = 0.016; odd ratio (OR): 2.55; 95% confidence interval (CI): 1.16-5.61), DRB1*010201 (P = 0.019; OR: 1.86; 95% CI: 1.10-3.15), and DRB1*1102 (P = 0.025; OR: 1.72; 95% CI: 1.07-2.78). DRB1*030201 (P = 0.038; OR: 0.48; 95% CI: 0.23-0.98), DRB1*070101 (P = 0.035; OR: 0.54; 95% CI: 0.30-0.97), DRB1*1503 (P = 0.0004; OR: 0.34; 95% CI: 0.19-0.64), and DRB5*010101 (P = 0.001; OR: 0.37; 95% CI: 0.20-0.67) were associated with susceptibility. The haplotype DRB1*1102-DRB3*020201 was associated with HIV-1 resistance (P = 0.041; OR: 1.68; 95% CI: 1.02-2.78), whereas the haplotypes DRB1*070101-DRB4*01010101 (P = 0.041; OR: 0.52; 95% CI: 0.28-0.98) and DRB1*1503-DRB5*01010101 (P = 0.0002; OR: 0.30; 95% CI: 0.15-0.58) were associated with susceptibility. These associations with resistance/susceptibility to HIV-1 were independent of previously reported alleles HLA-DRB1*01 and HLA-A*2301.
Our findings indicate that human leukocyte antigen DRB-specific CD4+ T-cell responses are an important factor in resistance/susceptibility to HIV-1 infection.
- SourceAvailable from: Natasja G De Groot[Show abstract] [Hide abstract]
ABSTRACT: In humans, great apes, and different monkey species, the major histocompatibility complex (MHC) class II DRB region is known to display considerable copy number variation. The microsatellite D6S2878 has been shown to be a valuable marker for haplotyping the DR region in humans and macaque species. The present report illustrates that chimpanzee haplotypes also can be discriminated with this marker. The analyses resulted in the description of nine different region configurations, of which seven are present within the West African chimpanzee population studied. The region configurations vary in gene content from two up to five DRB genes. Subsequent cDNA sequencing increased the number of known full-length Patr-DRB sequences from 3 to 32, and shows that one to three Patr-DRB genes per haplotype apparently produce functional transcripts. This is more or less comparable to humans and rhesus macaques. Moreover, microsatellite analysis in concert with full-length DRB gene sequencing showed that the Patr-DRB*W9 and -DRB3*01/02 lineages most likely arose from a common ancestral lineage: hence, the Patr-DRB*W9 lineage was renamed to Patr-DRB3*07. Overall, the data demonstrate that the D6S2878 microsatellite marker allows fast and accurate haplotyping of the Patr-DRB region. In addition, the limited amount of allelic variation observed at the various Patr-DRB genes is in agreement with the fact that chimpanzees experienced a selective sweep that may have been caused by an ancient retroviral infection.Molecular Immunology 10/2009; 47(2-3):381-9. DOI:10.1016/j.molimm.2009.09.003 · 3.00 Impact Factor
Conference Paper: ADMS - Automatic device model synthesizer[Show abstract] [Hide abstract]
ABSTRACT: This paper presents ADMS, a new open-source tool that supports automatic synthesis of compact models into circuit simulators. ADMS takes as input Verilog-AMS compact model descriptions and generates C code that conforms to circuit simulator interfaces. ADMS supports the simulators Mica, Spectre, and HSIM, and has been used to implement the SP and SSIM MOSFET models, the VBIC BJT model, and the R3 resistor model, the last two including self-heating.Custom Integrated Circuits Conference, 2002. Proceedings of the IEEE 2002; 02/2002