There is rapidly growing HIV literature, which has discovered a set of inherited genetic differences which can predict: a) the fraction of an infected population who will progress slowly, or never progress to AIDS symptoms (the so-called Elite Controllers), or b) the fraction of an infected population who will develop a dose limiting, Stevens-Johnson like inflammatory response to abacavir, and consequently, cannot be given that first-tier AIDS antiretroviral. The literature suggests that both of those effects are centered upon personalized variation within the HLA-B locus. Indeed, many now view the role of HLA-B in abacavir hypersensitivity and "Elite Controller" resistance to AIDS to be the gold standard for the entire field of personalized medicine. Based on this rapidly expanding role for HLA-B in personalized medicine, for AIDS and for conditions such as Stevens-Johnson syndrome & reactive arthritis (plus many others that are more speculative at present), we argue that the time is right to develop a simple, low-cost, one-pot genetic test which can be used for the analysis of all AIDS-relevant genetic variation in HLA-B, with a future eye to extending such HLA-B testing to encompass new indications in personalized medicine, as well. In this SBIR, we will use a novel microarray technology that we have invented to develop a specialized, very low cost microarray test, referred to as the "AIDS-Chip," which will perform very-high-resolution HLA-B testing as a single, simple, inexpensive, compact microarray test. This test will measure genetic factors of AIDS progression and therapeutic response embodied within the HLA-B locus in a way that can be expanded, later, into a more broadly-applicable HLA-B-based test for disease risk & pharmaceutical response in areas of medicine that might extend far beyond the AIDS focus of this SBIR. A key component of our AIDS-Chip is that it can be made highly redundant. It can encompass auxiliary genes such as KIR and CCR5, and importantly, can be coupled to high throughput, dry state sample collection on Guthrie cards in a way that, in Phase II, will be naturally suited for development of the AIDS-Chip as a low cost, ASHI-validated laboratory process and, with the FDA, as a 510K approved IVD.
Public Health Relevance: For at least twenty years, a basic understanding of the immune system would have required that personalized variation in the HLA gene cluster, especially Type I HLA genes, must give rise to some sort of personalized variation in the response to infection. However, the tools of the day were not sufficient to discover such (predicted) correlations in enough detail to be useful, nor to deploy that information in the field, as a public health test. However, based upon recent advancements in the tools of applied genetics, and driven by the severity of the disease, such explicit HLA correlations have emerged for AIDS and have been the basis for major excitement in the field. Thus, as had been predicted for many years, we are now entering an era where the methods of genetic testing can be applied, at the population scale, for HLA-based disease risk analysis. We argue that HIV-AIDS will be viewed as only the first of many such diseases, where heritable HLA variation can help predict life-long variation in disease risk. The technology to be developed in this SBIR will help deliver those newly discovered HLA-AIDS correlations, as a low-cost, population based genetic test. However, perhaps more importantly, a technology platform such as that which we will develop (a complex genetic test + dry state sample collection) will be viewed historically as a model for the way that population scale genetics will be used for all diseases in the decades to come. There is no doubt that, ten years from now, new technologies will emerge that are better, faster & cheaper than the AIDS-Chip that we will develop here. However, we are equally certain that, whatever those new population scale genetic tools may be, the way that they are used, will look very much like the "Guthrie Card + AIDS-Chip" pairing of this SBIR.
Public Health Relevance Statement: Public Health Narrative For at least twenty years, a basic understanding of the immune system would have required that personalized variation in the HLA gene cluster, especially Type I HLA genes, must give rise to some sort of personalized variation in the response to infection. However, the tools of the day were not sufficient to discover such (predicted) correlations in enough detail to be useful, nor to deploy that information in the field, as a public health test. However, based upon recent advancements in the tools of applied genetics, and driven by the severity of the disease, such explicit HLA correlations have emerged for AIDS and have been the basis for major excitement in the field. Thus, as had been predicted for many years, we are now entering an era where the methods of genetic testing can be applied, at the population scale, for HLA-based disease risk analysis. We argue that HIV-AIDS will be viewed as only the first of many such diseases, where heritable HLA variation can help predict life-long variation in disease risk. The technology to be developed in this SBIR will help deliver those newly discovered HLA-AIDS correlations, as a low-cost, population based genetic test. However, perhaps more importantly, a technology platform such as that which we will develop (a complex genetic test + dry state sample collection) will be viewed historically as a model for the way that population scale genetics will be used for all diseases in the decades to come. There is no doubt that, ten years from now, new technologies will emerge that are better, faster & cheaper than the AIDS-Chip that we will develop here. However, we are equally certain that, whatever those new population scale genetic tools may be, the way that they are used, will look very much like the "Guthrie Card + AIDS-Chip" pairing of this SBIR.
Project Terms: 21+ years old; AIDS; AIDS Virus; Accounting; Accreditation; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immune Deficiency Syndrome Virus; Acquired Immuno-Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Acquired Immunodeficiency Syndrome Virus; Adult; Alleles; Allelomorphs; Allergy; Anti-Retroviral Agents; Antiretroviral Agents; Applied Genetics; Area; Arizona; Arthritis, Postinfectious; Arthritis, Reactive; Au element; Automation; Blood; Blood Sample; Blood specimen; C-C CKR-5 Gene; C-C Chemokine Receptor Type 5 Gene; CC-CKR-5 Gene; CCCKR5 Gene; CCL3L1; CCL3L1 gene; CCR-5 Gene; CCR5; CCR5 gene; CD195 Antigen Gene; CHEMR13 Gene; CKR-5 Gene; CKR5 Gene; CMKBR5 Gene; Certification; Chemokine (C-C) Receptor 5 Gene; Clinic; Clinical; Clinical Evaluation; Clinical Testing; Collaborations; Collection; Complex; Computer Programs; Computer software; Coupled; Coupling; DNA; DNA Content; DNA Index; DNA Ploidy; DNA analysis; Data; Data Banks; Data Bases; Databank, Electronic; Databanks; Database, Electronic; Databases; Deoxyribonucleic Acid; Development; Development and Research; Diagnostic; Digit; Digit structure; Disease; Disorder; Dose-Limiting; Drops; Drugs; Elements; Ensure; Epidemiology; Erythema Multiforme Major; Ethics Committees, Research; Evaluation; Event; Eye; Eyeball; Family; Fingers; Freezing; Future; G0S19-2; Gene Cluster; Gene variant; Genes; Genetic; Genetic Diversity; Genetic Variation; Genetic screening method; Genomics; Goals; Gold; HIV; HIV-1 Fusion Co-Receptor Gene; HLA gene; HLA-A; HLA-A gene; HLA-B; HLA-B Antigens; HLAA; HTLV-III; Hereditary; Home; Home environment; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human, Adult; Hypersensitivity; IRBs; Immune system; Immunogenetic; Immunogenetics; Immunologic Deficiency Syndrome, Acquired; Individual; Infection; Inflammatory Response; Inherited; Ink; Institutional Review Boards; International; Knowledge; LAV-HTLV-III; LD78; LD78BETA; Laboratories; Letters; Life; Liquid substance; Literature; Lymphadenopathy-Associated Virus; Marketing; Measurable; Measures; Medical; Medication; Medicine; Methods; Microarray Analysis; Microarray-Based Analysis; Microscope; Modeling; Monitor; New Zealand; PAT 464.2; Performance; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Phase; Pilot Projects; Play; Ploidies; Population; Post-Infectious Arthritis; Price; Printing; Process; Production; Protocol; Protocols documentation; Public Health; R & D; R&D; Reaction; Reactive Arthritis; Reagent; Recovery; Reference Standards; Relative; Relative (related person); Research Ethics Committees; Research Specimen; Resistance; Resolution; Reticuloendothelial System, Blood; Risk; Role; Running; SBIR; SBIRS (R43/44); SCYA3L; SCYA3L1; Sampling; Science of Medicine; Services; Severity of illness; Site; Slide; Small Business Innovation Research; Small Business Innovation Research Grant; Software; Solutions; Sorting - Cell Movement; Specimen; Spottings; Stevens-Johnson Syndrome; Structure; Symptoms; Technology; Testing; Therapeutic; Time; Uncertainty; Universities; Validation; Variant; Variation; Variation (Genetics); Virus-HIV; Work; Ziagen; abacavir; adult human (21+); allelic variant; anti-retroviral; antiretroviral; base; body system, allergic/immunologic; chromosome complement; clinical data repository; clinical data warehouse; clinical test; computer program/software; cost; data repository; design; designing; disease risk; disease severity; disease/disorder; disorder risk; doubt; drug/agent; field study; fluid; genetic testing; human leukocyte antigen gene; interest; kamala; liquid; magnetic beads; manufacturing scale-up; meetings; microarray technology; new technology; novel; organ system, allergic/immunologic; pilot study; population based; pricing; prototype; public health medicine (field); public health relevance; relational database; research and development; research clinical testing; resistant; response; sample collection; scale up; social role; sorting; specimen collection; theories; tool
