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）：每次性行为感染 HIV 的概率较低，但与异性性行为相比，男男性行为者感染 HIV 的概率高 2 至 10 倍。鉴于感染早期病毒的遗传多样性有限，感染接种物中只有有限数量的病毒适合播种新的感染。这种适应性的部分原因在于通过 DC-SIGN、CD4 和 CCR-5 等已建立的受体将接种的病毒营养性与阴道、直肠或阴茎中的 HIV 靶细胞相匹配。肛交风险的增加无疑与靶细胞密度和可及性的差异有关。最近的研究指出，急性感染病毒中存在其他病毒包膜特征，例如异性传播中 A 型和 C 型病毒的包膜可变环缩短和糖基化模式改变，而在男男性行为者的 B 型病毒中未观察到这种模式。这些差异可能是由于与传播途径无关的亚型差异造成的，也可能是选择压力的结果，使得某些包络模式更适合异性传播而不是同性恋传播。为了澄清这些包膜基序是否与传播途径有关，当前的提案调查了特立尼达艾滋病毒异性传播群体急性/近期感染的 B 亚型病毒与阿根廷最近感染的同性恋男性的 B 亚型病毒。在感染时检查病毒准种，以及感染后 12 个月病毒在宿主体内适应时准种的进化，提供了一种了解包膜精细结构基序的方法，这些结构基序有助于通过异性与同性途径成功传播以及随后所需的适应用于持续感染。该研究将使用两个事件队列的存档样本。将使用从每个队列的血清转换时或之前获得的受试者 PBMC 中提取的 DNA 以及一年后在特立尼达队列中收集的样本来生成完整的包膜序列。模板的终点稀释将用于防止在表征病毒群体时出现偏差。 gp120 可变环的长度和糖基化将是比较的主要焦点，但还将检查包膜基因的其他相关特征。 项目叙述 当艾滋病毒通过性传播时，只有少数病毒真正进入并开始新的感染。他们中的大多数都被阻止了。如果我们更好地了解这是如何发生的，那么对于设计进一步阻止的代理会有很大帮助。这项研究检查了新感染者体内的病毒，以确定它们的共同点，这将提供线索，解释为什么他们进入而其他人却没有进入。