Biologic consequences of HIV-1 interaction with bacteria

HIV-1 与细菌相互作用的生物学后果

• 批准号: 10263148
• 负责人: Catarina E Hioe
• 金额: $ 25.7万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263148
• 关键词: Acquired Immunodeficiency Syndrome; Adherence; Affect; Affinity; Anal Sex; Anti-Retroviral Agents; Antiviral Agents; Apical; Applications Grants; Bacteria; Bacterial Vaginosis; Bacteriuria; Binding; Biochemistry; Biological; Biological Factors; Cells; Cessation of life; Chitra; Chlamydia; Clinical; Consequences of HIV; Data; Epidemic; Escherichia coli; Exposure to; General Population; Genitourinary system; Glycoproteins; Goals; Gonorrhea; HIV; HIV-1; Heterosexuals; Human; Immunity; In Vitro; Individual; Infant; Infection; Inflammation; Inflammatory; Intestines; Lectin; Life; Mannose Binding Lectin; Mediating; Microbe; Molecular; Mucous Membrane; Names; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacology; Polysaccharides; Prevalence; Prevention; Preventive vaccine; Probability; Property; Proteins; Risk; Route; Sexual Partners; Sexual Transmission; Sexually Transmitted Diseases; Surface; Syphilis; Testing; Urinary tract infection; Urology; Uropathogenic E. coli; Urothelium; Vaccines; Vagina; Viral; Virion; Virus; Virus Diseases; antiretroviral therapy; base; design; experimental study; fimbria; humanized mouse; in vivo; injection drug use; innovation; insight; interest; medical schools; men who have sex with men; microbial; microbicide; mouse model; mucosal site; novel; novel strategies; penis; prevent; prophylactic; recruit; rectal HIV transmission; sexual HIV transmission; transmission process; urogenital tract; virus envelope

Summary/Abstract In the era of potent antiretroviral therapy (ART), the rates of new HIV-1 infection and AIDS-associated death have declined worldwide. Nonetheless, an estimated total of 1.8 million people became newly infected in 2017. Current ART fails to clear the virus, and thus life-long adherence to treatment is necessary for individuals living with HIV-1. Prevention is essential to stop this global epidemic, but no prophylactic vaccines or microbicides are currently available. A better understanding of key determinants influencing HIV-1 transmission is needed for developing innovative, efficacious strategies to prevent HIV-1 acquisition. The most common route of HIV-1 transmission is via sexual contact, especially during penile-vaginal and penile-anal intercourse. Many biologic factors that increase the probability of sexual HIV-1 transmission have been studied, including microbial perturbation associated with bacterial vaginosis and with sexually transmitted diseases caused by viruses and bacteria. The reason for this enhanced transmission is commonly thought to be increased inflammation and recruitment of activated, highly permissive target cells to the mucosal sites in the donor or the recipient. However, little is known about the biologic consequences of HIV-1 interaction with bacteria. Our preliminary study demonstrated that HIV-1 can bind to E. coli via the interaction of HIV-1 envelope (Env) N-glycans with FimH, a mannose-specific lectin expressed on the fimbria of uropathogenic E. coli that can colonize the genitourinary tract and cause urinary tract infection. Importantly, unlike the antiviral properties of other lectins with binding affinity for Env, FimH interaction does not interfere with and may even enhance HIV-1 infectivity. Based on these data, we propose a novel hypothesis that a direct interaction between HIV-1 and certain bacteria present in the genitourinary mucosa promotes virus infectivity and transmissibility. To test this hypothesis, we will first perform in vitro experiments to examine the interaction of HIV-1 Env from major clades, especially Env of transmitter/founder strains, with FimH protein and FimH-bearing E. coli, and then we will assess how such an interaction affects virus stability and transmissibility to target cells (Aim 1). Subsequently, we will use a humanized mouse model to determine whether mucosal exposure to HIV-1 in conjunction with FimH-bearing E. coli enhances the likelihood for HIV-1 acquisition (Aim 2). As a result of the proposed study, we expect to gain a better understanding of the importance of direct HIV-1 interaction with bacteria in determining the efficiency of mucosal transmission of HIV-1. These data will provide valuable insights into and clinically practical leads toward new approaches to decreasing the risk of HIV-1 sexual transmission.

总结/摘要 在有效的抗逆转录病毒疗法（ART）时代，新的HIV-1感染率和艾滋病相关死亡率 在全球范围内都在下降。尽管如此，2017年估计共有180万人新感染。 目前的抗逆转录病毒疗法无法清除病毒，因此，对于生活在艾滋病病毒/艾滋病病毒/艾滋病患者来说，终生坚持治疗是必要的。 HIV-1预防是阻止这一全球流行病的关键，但没有预防性疫苗或杀微生物剂， 目前可用。需要更好地了解影响HIV-1传播的关键决定因素， 制定创新的、有效的策略来预防HIV-1感染。HIV-1最常见的传播途径 通过性接触传播，特别是在阴茎-阴道和阴茎-肛门性交期间。多种生物 增加HIV-1性传播可能性的因素已被研究，包括微生物 与细菌性阴道病和由病毒引起的性传播疾病有关的扰动， 细菌这种增强传播的原因通常被认为是炎症增加， 将活化的、高容许性的靶细胞募集到供体或受体的粘膜部位。 然而，对HIV-1与细菌相互作用的生物学后果知之甚少。 我们的初步研究表明HIV-1可以与E.通过HIV-1包膜的相互作用 (Env)FimH是一种甘露糖特异性凝集素，表达于尿路致病性大肠杆菌菌毛上。大肠杆菌， 寄生在泌尿生殖道并引起尿路感染。重要的是，与抗病毒特性不同， 其它对Env、FimH相互作用具有结合亲和力的凝集素不干扰甚至可增强HIV-1 传染性基于这些数据，我们提出了一个新的假设，即HIV-1和 泌尿生殖道粘膜中存在的某些细菌会促进病毒的传染性和传播性。为了验证这一 假设，我们将首先进行体外实验以检查来自主要进化枝的HIV-1 Env的相互作用， 尤其是传递者/创始者菌株的Env与FimH蛋白和携带FimH的E.大肠杆菌，然后我们 评估这种相互作用如何影响病毒稳定性和向靶细胞的传播性（目标1）。随后，委员会注意到， 我们将使用人源化小鼠模型来确定粘膜暴露于HIV-1是否与 含FimH的E.大肠杆菌增加了HIV-1感染的可能性（目的2）。由于拟议的研究， 我们希望能更好地了解HIV-1与细菌直接相互作用的重要性， 确定HIV-1粘膜传播的效率。这些数据将提供有价值的见解， 临床实践导致新的方法来降低HIV-1性传播的风险。