HIV-1 subtype B transmission in a heterosexual incident cohort

HIV-1 B 亚型在异性恋事件队列中的传播

• 批准号: 7655419
• 负责人: JEAN K CARR
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7655419
• 关键词: Acute; Address; Amino Acids; Anus; Archives; Argentina; CCR5 gene; Cell Density; Cells; Cercopithecine Herpesvirus 1; Characteristics; Chemokine (C-C Motif) Receptor 5; Code; Complement component C1s; Computer software; DNA; Dendritic Cells; Elements; Evolution; Genes; Genetic; Genetic Variation; Goals; Growth; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; Heterosexuals; Homosexuals; Incidence Study; Infection; Lamina Propria; Lead; Length; Life Cycle Stages; Link; Mucous Membrane; Natural Selections; Nature; Patients; Pattern; Peripheral Blood Mononuclear Cell; Persons; Population; Prevention; Prevention strategy; Probability; Rectum; Research; Risk; Route; Sampling; Scanning; Seeds; Sexual Transmission; Site; Specific qualifier value; Specimen; Testing; Time; Tobago; Trinidad; United States National Institutes of Health; Vaccines; Vagina; Variant; Viral; Virus; Virus Diseases; Virus Receptors; cohort; design; fitness; glycosylation; insight; interest; men; men who have sex with men; microbicide; patient population; penis; pressure; prevent; programs; receptor; rectal; sex; therapy design; tool; transmission process

DESCRIPTION (provided by applicant): The per sex act probability of acquiring HIV infection is low but 2- to 10-fold higher in men who have sex with men compared to heterosexual transmission. Given the narrow genetic diversity of virus early in infection only a limited number of viruses in the infecting innoculum are fit to seed the new infection. Part of this fitness relates to matching inoculated viral trophisms to the HIV target cell in the vagina, rectum, or penis through established receptors such as DC-SIGN, CD4 and CCR-5. Heighten risk in the context of anal intercourse is undoubtedly associated with differences in target cell density and accessibility. Recent studies point to additional viral envelope characteristics in acute infection viruses such as shortened envelope variable loops and altered glycosylation patterns in subtype A and C viruses in heterosexual transmission, a pattern not observed in subtype B from men who have sex with men. These differences could result from subtype differences unrelated to transmission route or could be a result of selection pressure, making certain envelope patterns more fit for heterosexual versus homosexual transmission. To clarify whether these envelope motifs are linked to route of transmission the current proposal investigates subtype B viruses from acute/recent infection from an HIV heterosexual transmission cohort from Trinidad compared to subtype B viruses from recently infected homosexual men in Argentina. Examination of viral quasispecies at the time of infection and evolution of quasispecies as the virus adapts in the host 12 months after infection provide a means of understanding fine structural motifs of the envelope that contribute to successful transmission via heterosexual versus homosexual routes and the subsequent adaptation required for sustained infection. The study will use archived samples from two incident cohorts. Complete envelope sequences will be generated using extracted DNA from subject PBMC acquired at or before seroconversion in each of the cohorts and samples collected 1 year later in the Trinidad cohort. End-point dilution of template will be used to prevent bias in characterizing the viral population. The length and glycosylation of the variable loops of gp120 will be the primary focus of the comparison, but other relevant features of the envelope gene will also be examined.Project Narrative When HIV is sexually transmitted, only a few of the viruses actually get in to start a new infection; most of them are blocked. If we had a better understanding of how that happens, it would help a great deal in designing agents to block even further. This study examines the viruses in newly infected people to determine what they have in common that would provide a clue about why they gained entry while others did not.

描述（由申请人提供）：与异性恋传播相比，与男性发生性关系的男性，获得HIV感染的PER ACT概率低2至10倍。鉴于感染早期病毒的遗传多样性狭窄，只有有限数量的Innoculum病毒可用于播种新的感染。这种适应性的一部分与通过已建立的受体（例如DC-SIGN，CD4和CCR-5）相匹配的接种病毒营养物与阴道，直肠或阴茎中的HIV靶细胞有关。在肛交的背景下，增加风险无疑与目标细胞密度和可及性的差异有关。最近的研究指出，急性感染病毒中的其他病毒包膜特征，例如缩短的包膜可变环和异性传播亚型A和C病毒中的糖基化模式改变，这种模式在与男性发生性关系的男性中未观察到的模式。这些差异可能是由于与传输途径无关的亚型差异而导致的，也可能是选择压力的结果，使某些包膜模式更适合异性恋与同性恋传播。为了阐明这些包膜基序是否与传播途径有关，目前的提案研究了来自特立尼达的HIV异性传播队列的急性/最近感染的亚型B病毒，与最近感染的阿根廷同性恋男性的亚型B病毒相比。在感染和准菜的演化时，检查病毒准则在感染后12个月适应了宿主中的病毒，这提供了一种理解信封的精细结构基序，这些基序有助于通过异性恋与同性恋途径和后续适应进行持续感染的良好传播。该研究将使用来自两个事件队列的存档样品。将使用从每个队列中或在血清转化之前获得的受试者PBMC提取的DNA生成完整的包膜序列，并在1年后在特立尼达队列中收集的样品。模板的终点稀释将用于防止偏向病毒种群的偏见。 GP120变量回路的长度和糖基化将是比较的主要重点，但是也将检查信封基因的其他相关特征。 当艾滋病毒发生性传播时，只有少数病毒实际上开始了新的感染。他们中的大多数被阻止。如果我们对这种情况有更好的了解，那将有助于设计代理商进一步阻止代理。这项研究检查了新感染的人的病毒，以确定他们的共同点，以提供有关为什么他们进入而其他人没有的线索。