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Trivalent adenovirus type 5 HIV recombinant vaccine primes for modest cytotoxic capacity that is greatest in humans with protective HLA class I alleles.

ABSTRACT: If future HIV vaccine design strategies are to succeed, improved understanding of the mechanisms underlying protection from infection or immune control over HIV replication remains essential. Increased cytotoxic capacity of HIV-specific CD8+ T-cells associated with efficient elimination of HIV-infected CD4+ T-cell targets has been shown to distinguish long-term nonprogressors (LTNP), patients with durable control over HIV replication, from those experiencing progressive disease. Here, measurements of granzyme B target cell activity and HIV-1-infected CD4+ T-cell elimination were applied for the first time to identify antiviral activities in recipients of a replication incompetent adenovirus serotype 5 (Ad5) HIV-1 recombinant vaccine and were compared with HIV-negative individuals and chronically infected patients, including a group of LTNP. We observed readily detectable HIV-specific CD8+ T-cell recall cytotoxic responses in vaccinees at a median of 331 days following the last immunization. The magnitude of these responses was not related to the number of vaccinations, nor did it correlate with the percentages of cytokine-secreting T-cells determined by ICS assays. Although the recall cytotoxic capacity of the CD8+ T-cells of the vaccinee group was significantly less than that of LTNP and overlapped with that of progressors, we observed significantly higher cytotoxic responses in vaccine recipients carrying the HLA class I alleles B*27, B*57 or B*58, which have been associated with immune control over HIV replication in chronic infection. These findings suggest protective HLA class I alleles might lead to better outcomes in both chronic infection and following immunization due to more efficient priming of HIV-specific CD8+ T-cell cytotoxic responses.

SUBMITTER: Migueles SA

PROVIDER: S-EPMC3044701 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Trivalent adenovirus type 5 HIV recombinant vaccine primes for modest cytotoxic capacity that is greatest in humans with protective HLA class I alleles.

Migueles Stephen A SA Rood Julia E JE Berkley Amy M AM Guo Tiffany T Mendoza Daniel D Patamawenu Andy A Hallahan Claire W CW Cogliano Nancy A NA Frahm Nicole N Duerr Ann A McElrath M Juliana MJ Connors Mark M

PLoS pathogens 20110224 2

If future HIV vaccine design strategies are to succeed, improved understanding of the mechanisms underlying protection from infection or immune control over HIV replication remains essential. Increased cytotoxic capacity of HIV-specific CD8+ T-cells associated with efficient elimination of HIV-infected CD4+ T-cell targets has been shown to distinguish long-term nonprogressors (LTNP), patients with durable control over HIV replication, from those experiencing progressive disease. Here, measuremen ...[more]

PMID: 21383976

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Project description:A recent genome-wide association study (GWAS) suggested that polymorphisms in or around the genes HCP5, HLA-C and ZNRD1 confer restriction against HIV-1 viral replication or disease progression. Here, we also find that these alleles are associated with different aspects of HIV disease, albeit mainly in European Americans. Additionally, we offer that because the GWAS cohort was a subset of HIV-positive individuals, selected based in part on having a low viral load, the observed associations for viral load are magnified compared with those we detect in a large well-characterized prospective natural history cohort of HIV-1-infected persons. We also find that because of linkage disequilibrium (LD) patterns, the dominant viral load- and disease-influencing associations for the ZNRD1 or HLA-C and HCP5 alleles are apparent mainly when these alleles are present in HLA-A10- or HLA-B*57-containing haplotypes, respectively. ZNRD1 alleles lacking HLA-A10 did not confer disease protection whereas ZNRD1-A10 haplotypes did. When examined in isolation, the HCP5-G allele associates with a slow disease course and lower viral loads. However, in multivariate models, after partitioning out the protective effects of B*57, the HCP5-G allele associates with disease-acceleration and enhanced viral replication; these associations for HCP5-G are otherwise obscured because of the very strong LD between this allele and a subset of protective B*57 alleles. Furthermore, HCP5 and HLA-C alleles stratify B*57-containing genotypes into those that associate with either striking disease retardation or progressive disease, providing one explanation for the long-standing conundrum of why some HLA-B*57-carrying individuals are long-term non-progressors, whereas others exhibit progressive disease. Collectively, these data generally underscore the strong dependence of genotype-phenotype relationships upon cohort design, phenotype selection, LD patterns and populations studied. They specifically demonstrate that the influence of ZNRD1 alleles on disease progression rates are attributable to HLA-A10, help clarify the relationship between the HCP5, HLA-C and HLA-B*57 alleles, and reaffirm a critical role of HLA-B*57 alleles in HIV disease. Furthermore, as the protective B*57-containing genotypes convey striking salutary effects independent of their strong impact on viral control, it is conceivable that T cell-based therapeutic vaccine strategies aimed at reducing viral loads may be inadequate for limiting AIDS progression, raising the potential need for complementary strategies that target viral load-independent determinants of pathogenesis.

Project description:Accurate and full-length typing of the HLA region is important in many clinical and research settings. With the advent of next generation sequencing (NGS), several HLA typing algorithms have been developed, including many that are applicable to whole exome sequencing (WES). However, most of these solutions operate by providing the closest-matched HLA allele among the known alleles in IPD-IMGT/HLA Database. These database-matching approaches have demonstrated very high performance when typing well characterized HLA alleles. However, as they rely on the completeness of the HLA database, they are not optimal for detecting novel or less well characterized alleles. Furthermore, the database-matching approaches are also not adequate in the context of cancer, where a comprehensive characterization of somatic HLA variation and expression patterns of a tumor's HLA locus may guide therapy and clinical outcome, because of the pivotal role HLA alleles play in tumor antigen recognition and immune escape. Here, we describe a personalized HLA typing approach applied to WES data that leverages the strengths of database-matching approaches while simultaneously allowing for the discovery of novel HLA alleles and tumor-specific HLA variants, through the systematic integration of germline and somatic variant calling. We applied this approach on WES from 10 metastatic melanoma patients and validated the HLA typing results using HLA targeted NGS sequencing from patients where at least one HLA germline candidate was detected on Class I HLA. Targeted NGS sequencing confirmed 100% performance for the 1st and 2nd fields. In total, five out of the six detected HLA germline variants were because of Class I ambiguities at the third or fourth fields, and their detection recovered the correct HLA allele genotype. The sixth germline variant let to the formal discovery of a novel Class I allele. Finally, we demonstrated a substantially improved somatic variant detection accuracy in HLA alleles with a 91% of success rate in simulated experiments. The approach described here may allow the field to genotype more accurately using WES data, leading to the discovery of novel HLA alleles and help characterize the relationship between somatic variation in the HLA region and immunosurveillance.

Dataset Information

Trivalent adenovirus type 5 HIV recombinant vaccine primes for modest cytotoxic capacity that is greatest in humans with protective HLA class I alleles.

Publications

Trivalent adenovirus type 5 HIV recombinant vaccine primes for modest cytotoxic capacity that is greatest in humans with protective HLA class I alleles.

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