Proj. 4-The Genetic Variation of Innate Immune Genes w/Oral Manifestations of HIV

项目。

• 批准号: 8377539
• 负责人: Peter A Zimmerman
• 金额: $ 31.42万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8377539
• 关键词: 11p; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Africa; African American; Agonist; Aphthous Stomatitis; Area; Autoimmune Diseases; Bacteria; CD4 Positive T Lymphocytes; CXCR4 gene; Candidiasis; Cause of Death; Cells; Cessation of life; Chemotaxis; Child; Communicable Diseases; Complex; Complication; Cytomegalovirus; DEFB1 gene; Defensins; Development; Disease; Disease Progression; Disease susceptibility; Economic Factors; Effectiveness; Environment; Epidemic; Epithelial; Epithelial Cells; Ethnic Origin; Family; Family member; Frequencies; Gene Cluster; Gene Dosage; Gene Family; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; HIV; HIV Infections; HIV Seropositivity; Hairy Leukoplakia; Haplotypes; Highly Active Antiretroviral Therapy; Host Defense; Human; Human Papillomavirus; Immune; Immune System Diseases; Immune response; Immune system; Immunosuppression; Incidence; Individual; Infection; Inflammation Mediators; Inflammatory; Kaposi Sarcoma; Maintenance; Mediating; Microbe; Mothers; Mucosal Immunity; Natural Immunity; Opportunistic Infections; Oral; Oral Manifestations; Oral candidiasis; Oral cavity; Oral mucous membrane structure; Outcome; Pathology; Patients; Peptides; Periodontitis; Play; Population; Predisposition; Process; Property; Race; Risk; Role; Signal Transduction; Simplexvirus; Single Nucleotide Polymorphism; Stomatitis; Structure; Surface; TLR1 gene; Tissues; Toll-like receptors; Up-Regulation; Variant; Vertical Disease Transmission; Viral; Virus; antimicrobial; beta-Defensins; fungus; member; microbial; oral infection; oral lesion; oral wart; outcome forecast; receptor; response; socioeconomics; treatment response; 11p; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Africa; African American; Agonist; Aphthous Stomatitis; Area; Autoimmune Diseases; Bacteria; CD4 Positive T Lymphocytes; CXCR4 gene; Candidiasis; Cause of Death; Cells; Cessation of life; Chemotaxis; Child; Communicable Diseases; Complex; Complication; Cytomegalovirus; DEFB1 gene; Defensins; Development; Disease; Disease Progression; Disease susceptibility; Economic Factors; Effectiveness; Environment; Epidemic; Epithelial; Epithelial Cells; Ethnic Origin; Family; Family member; Frequencies; Gene Cluster; Gene Dosage; Gene Family; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; HIV; HIV Infections; HIV Seropositivity; Hairy Leukoplakia; Haplotypes; Highly Active Antiretroviral Therapy; Host Defense; Human; Human Papillomavirus; Immune; Immune System Diseases; Immune response; Immune system; Immunosuppression; Incidence; Individual; Infection; Inflammation Mediators; Inflammatory; Kaposi Sarcoma; Maintenance; Mediating; Microbe; Mothers; Mucosal Immunity; Natural Immunity; Opportunistic Infections; Oral; Oral Manifestations; Oral candidiasis; Oral cavity; Oral mucous membrane structure; Outcome; Pathology; Patients; Peptides; Periodontitis; Play; Population; Predisposition; Process; Property; Race; Risk; Role; Signal Transduction; Simplexvirus; Single Nucleotide Polymorphism; Stomatitis; Structure; Surface; TLR1 gene; Tissues; Toll-like receptors; Up-Regulation; Variant; Vertical Disease Transmission; Viral; Virus; antimicrobial; beta-Defensins; fungus; member; microbial; oral infection; oral lesion; oral wart; outcome forecast; receptor; response; socioeconomics; treatment response

Oral manifestations of HIV have been documented since the initial presentation of the HIV/AIDS epidemic of the 80's. The most common oral complication was candidiasis, and was associated with a reduction in CD4+T cells. Oral candidal infection was a hallmark indicator of immune dysfunction. The increased incidence of opportunistic infections was related to immune suppression as evidenced by a reduction in number and functional activity of CD4 + T cells. The frequency and type of oral complication has changed since the initial description of the 80s. With the initiation of HAART therapies the constellation of oral manifestations has changed. The incidence of HPV associated warts and severe aphthous ulcer stomatitis has increased, whereas oral candidal infection and oral hairy leukoplakia has declined. In addition, not all patients develop these pathologies. The variation in disease presentation and concomitant response to therapy may be related to genetic predisposition of innate immune genes and variation in epithelial barrier function. Innate immunity is increasingly being recognized as playing a critical role in host defense against infectious diseases, including HIV. The defensin peptides have antimicrobial properties and are major protective components of the epithelial mucosal barrier. Genetic variation of the defensin genes in the form of SNPs and CNVs has been shown to be associated with disease susceptibility. Toll-like receptors (TLRs), a family of evolutionary conserved receptors on host cells including human oral epithelial cells, recognize specific microbial structures, leading to the up-regulation of inflammatory mediators and recruitment of inflammatory cells. Multiple interactions of microbes and host tissues and secreted antimicrobial molecules such as beta-defensins are involved in the maintenance of the homeostatic environment of the healthy mouth, however, little is known about the role of TLRs in this process or the impact of HIV disease on these processes. Polymorphisms in the TLR family and the common adaptor Tirap/Mal have been associated with many human infectious and autoimmune diseases. We hypothesize that host variation in TLRs and their signaling components contribute to the variability in oral infections seen in HIV disease by altering host/microbe interactions at the mucosal surface. We will decipher the relationship of genetic variations in both the defensin gene cluster and toll-like receptors TLR1 and 2 with oral manifestations of HIV/AIDS. We will define and correlate specific complex haplotypes with the frequency and occurrence of oral lesions in the HIV population. We hypothesize that susceptibility, prognosis, and outcome of HIV are associated with genetic variations in the defensin gene cluster. This same variation also may be associated with the development of oral complications following HIV infection

自艾滋病毒/艾滋病流行病初次介绍以来，已经记录了艾滋病毒的口服表现。 80年代。最常见的口服并发症是念珠菌病，与降低有关 CD4+T细胞。口服候选感染是免疫功能障碍的标志指标。增加 机会性感染的发病率与免疫抑制有关，从而降低了 CD4 + T细胞的数量和功能活性。口服并发症的频率和类型已经改变 自80年代的最初描述以来。随着HAART疗法的启动，口服星座 表现发生了变化。 HPV相关疣的发生率和严重的冬季溃疡性气孔炎 口服候选感染和口服毛状白血球的增加，已经有所增加。另外，不是全部 患者发展了这些病理。疾病表现的差异和对 治疗可能与先天免疫基因的遗传倾向和上皮屏障的变异有关 功能。先天免疫越来越被认为是在宿主防御中发挥关键作用 传染病，包括艾滋病毒。防御素肽具有抗菌特性，是主要的 上皮粘膜屏障的保护性成分。防御素基因的遗传变异形式 SNP和CNV已被证明与疾病易感性有关。 Toll样受体（TLR）， 包括人口腔上皮细胞在内的宿主细胞上的进化保守受体家族，识别 特定的微生物结构，导致炎症介质的上调和募集 炎性细胞。微生物和宿主组织的多种相互作用以及分泌的抗菌分子 例如β-防御素参与健康的稳态环境 然而，对TLR在此过程中的作用或HIV疾病对这些的影响知之甚少 过程。 TLR家族和常见适配器Tirap/Mal的多态性与 许多人类感染和自身免疫性疾病。我们假设TLR中的宿主变化及其 信号传导成分通过改变而导致艾滋病毒疾病中口腔感染的变异性 粘膜表面的宿主/微生物相互作用。我们将破译遗传变异的关系 艾滋病毒/艾滋病的口服表现，防御素基因簇和Toll样受体TLR1和2。我们 将定义并将特定的复合型单倍型与口服病变的频率和出现 艾滋病毒人群。我们假设艾滋病毒的敏感性，预后和结果与 防御素基因簇中的遗传变异。同样的变化也可能与 艾滋病毒感染后口服并发症的发展