Vaccine-induced HIV-specific CD8+ T cells utilize preferential HLA alleles and target-specific regions of HIV-1

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
JAIDS Journal of Acquired Immune Deficiency Syndromes (Impact Factor: 4.56). 06/2011; 58(3):248-52. DOI: 10.1097/QAI.0b013e318228f992
Source: PubMed


Most T cell-based HIV-1 vaccine candidates induce responses of limited breadth for reasons that are unclear. We evaluated vaccine-induced T-cell responses in individuals receiving an HIV-1 recombinant adenoviral vaccine. Certain HLA alleles (B27, B57, B35, and B14) are preferentially utilized to mount HIV-specific responses, whereas other alleles (A02 and B07) are rarely utilized (P < 0.001). This preference seems due to 4 following factors individually or in combination: higher affinity of specific peptides to specific HLA alleles; higher avidity of T-cell receptor; HLA and peptide interaction; and/or higher surface expression of certain HLA. Thus, HLA immunodominance plays a substantial role in vaccine-induced T-cell responses.

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    • "Non-synonymous allelic variants of HLA gene products can bind distinct antigenic peptides [10,11], be subject to differential regulation [12,13], and have varied interactions with T-Cell Receptors [14], Killer Immunoglobulin-like Receptors[15] and viral proteins [16]. The direct link between HLA polymorphism and various diseases is a subject of intensive investigation, with hundreds of published studies every year. "
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    ABSTRACT: Background High-resolution HLA genotyping is a critical diagnostic and research assay. Current methods rarely achieve unambiguous high-resolution typing without making population-specific frequency inferences due to a lack of locus coverage and difficulty in exon-phase matching. Achieving high-resolution typing is also becoming more challenging with traditional methods as the database of known HLA alleles increases. Results We designed a cDNA amplicon-based pyrosequencing method to capture 94% of the HLA class I open-reading-frame with only two amplicons per sample, and an analogous method for class II HLA genes, with a primary focus on sequencing the DRB loci. We present a novel Galaxy server-based analysis workflow for determining genotype. During assay validation, we performed two GS Junior sequencing runs to determine the accuracy of the HLA class I amplicons and DRB amplicon at different levels of multiplexing. When 116 amplicons were multiplexed, we unambiguously resolved 99%of class I alleles to four- or six-digit resolution, as well as 100% unambiguous DRB calls. The second experiment, with 271 multiplexed amplicons, missed some alleles, but generated high-resolution, concordant typing for 93% of class I alleles, and 96% for DRB1 alleles. In a third, preliminary experiment we attempted to sequence novel amplicons for other class II loci with mixed success. Conclusions The presented assay is higher-throughput and higher-resolution than existing HLA genotyping methods, and suitable for allele discovery or large cohort sampling. The validated class I and DRB primers successfully generated unambiguously high-resolution genotypes, while further work is needed to validate additional class II genotyping amplicons.
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    ABSTRACT: We encounter pathogens on a daily basis and our immune system has evolved to mount an immune response following an infection. An interesting phenomenon that has evolved in response to clearing bacterial and viral infections is called immunodominance. Immunodominance refers to the phenomenon that, despite co-expression of multiple major histocompatibility complex class I alleles by host cells and the potential generation of hundreds of distinct antigenic peptides for recognition following an infection, a large portion of the anti-viral cytotoxic T lymphocyte population targets only some peptide/MHC class I complexes. Here we review the main factors contributing to immunodominance in relation to influenza A and HIV infection. Of special interest are the factors contributing to immunodominance in humans and rodents following influenza A infection. By critically reviewing these findings, we hope to improve understanding of the challenges facing the discovery of new factors enabling better anti-viral vaccine strategies in the future.
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