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The push and pull of inflammation on HIV susceptibility: impact of host variation in CD101 and AXL

炎症对 HIV 易感性的推拉：CD101 和 AXL 宿主变异的影响

基本信息

批准号：
10546199
负责人：
Florian Hladik
金额：
$ 81.52万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-12 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10546199
关键词：
Accounting Africa African Archives Autophagocytosis Biological Biological Specimen Banks Blood Blood Cells CD8-Positive T-Lymphocytes Cell Nucleus Cells Colitis Counseling Cryopreservation Data Diabetes Mellitus Disease Epidemiology Equilibrium Exhibits Exposure to Genes Genetic Genital Genitalia Genome Genotype HIV HIV risk HIV-1 Heterosexuals Highly Active Antiretroviral Therapy Homeostasis Immune Immunoglobulin Domain Immunologics In Vitro Individual Infection Inflammasome Inflammation Inflammatory Inflammatory Response Innate Immune Response Interferons Interleukin-2 Intervention Knowledge Lead Link Mediating Medicine Molecular Mucous Membrane Mus Myeloid Cells Natural Resistance Nuclear Translocation Outcome Pathway interactions Peripheral Blood Mononuclear Cell Persons Phenotype Population Predisposition Prevention approach Production Public Health RNA Splicing Receptor Protein-Tyrosine Kinases Regulation Regulatory T-Lymphocyte Reporting Research Personnel Resistance Risk Sampling Single Nucleotide Polymorphism Site T-Cell Activation T-Lymphocyte Techniques Testing Tissues Toll-like receptors United States Untranslated Regions Variant Woman base base editing cell type chemokine cohort cytokine density ethnic diversity female sex worker genetic variant genital infection genome editing genomic data hazard high risk high risk men immune activation infection risk macrophage men who have sex with men monocyte novel novel strategies nuclear factors of activated T-cells pandemic disease pathogen pre-exposure prophylaxis prevent programs protective allele recruit risk variant sample archive trait transcription factor transcriptome vaginal mucosa

项目摘要

ABSTRACT Despite the significant public health impact of highly active antiretroviral therapy and pre-exposure prophylaxis on the HIV-1 pandemic, fundamental questions remain about the biological mechanisms that define the risk of sexually acquiring HIV-1. Notably, there is no explanation why, after accounting for genetic variants that directly modify HIV-1 entry and replication (foremost CCR5Δ-32), individuals with documented high exposure to HIV- 1 exhibit diverse outcomes ranging from rapid infection to prolonged natural resistance to HIV-1 infection. A better understanding of these phenotypes could lead to novel interventions to reduce HIV-1 acquisition. We previously identified functional variants (missense/nonsense, untranslated region, or splice site) in host genes that are strongly associated with altered risk of heterosexually acquired HIV-1 infection. Notably, genetic variants in CD101 had the strongest association with increased HIV-1 risk, while variants in AXL had substantially reduced risk. Both genes are thought to regulate host inflammatory responses. CD101 regulates T cell activation and is expressed on many immune cell types. We recently reported that circulating T cells and monocytes from donors with these CD101 variants, compared to donors without functional CD101 variants, show higher overall cellular activation, but with reduced expression of certain HIV-protective interferon stimulated genes. In contrast, AXL is a receptor tyrosine kinase thought to act through myeloid cells to inhibit cellular immune activation, possibly through inhibition of toll-like receptor-mediated innate immune responses. Our overarching hypothesis is that host variation in CD101 and AXL genotypes contributes to altered inflammatory homeostasis, thereby influencing the risk of HIV-1 infection. Specifically, we hypothesize that CD101 variants confer a higher risk of HIV-1 infection by increasing the abundance and activation of HIV-1 susceptible T cells, while also compromising their innate antiviral defenses. Conversely, the absence of these variants, possibly augmented by reduced inflammation conferred by AXL variants, lowers HIV-1 infection risk. We propose to evaluate our hypothesis in three aims: in Aim 1, we use genomic data from a cohort with well- characterized HIV-1 acquisition phenotypes to replicate in a second high HIV-risk African cohort that AXL variants balance the impact of CD101 variants on HIV-1 susceptibility. In Aim 2, we test the epidemiological and population generalizability of our hypothesis by quantifying the association of CD101 and AXL variation with susceptibility to HIV-1 infection in two US populations for which genomic data already exist: one that includes predominantly white men who have sex with men; and a second, ethnically diverse cohort recruited across the entire US. In Aim 3, we apply molecular techniques to blood and genital mucosal samples archived in a unique biospecimen repository to directly link the presence of these CD101 and AXL variants with host inflammatory mechanisms, and ex vivo HIV-1 susceptibility.

摘要