Viral Evolution and Humoral Immune Response to Dual HIV-1 Infection

双重 HIV-1 感染的病毒进化和体液免疫反应

• 批准号: 8261115
• 负责人: Phillipe N Nyambi
• 金额: $ 47.66万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261115
• 关键词: African; Antibodies; Antigens; Antiviral Agents; Autologous; Biological Assay; Blood; Cameroon; Central Africa; Characteristics; Clinical; Country; Diagnosis; Disease; Epitopes; Evolution; Exhibits; Generations; HIV; HIV-1; Immune response; Immune system; Immunity; Individual; Infection; Knowledge; Light; Monoclonal Antibodies; Parents; Pathogenesis; Patients; Pattern; Pharmaceutical Preparations; Plasma; Population; Predisposition; Recombinants; Resistance; Sampling; Sequence Analysis; Serum; Specimen; Testing; Time; Vaccine Design; Vaccines; Variant; Viral; Viral Antigens; Virus; Work; dual diagnosis; genetic evolution; improved; neutralizing antibody; public health relevance; recombinant virus

DESCRIPTION (provided by applicant): In regions of the world like West-Central Africa where multiple HIV-1 groups and subtypes co-circulate, the rate of dual infection - the concomitant or sequential infection with two or more genetically distinct HIV-1 strains is frequent, and recombinant viruses are common. A key characteristic of HIV-1 is its ability to recombine following dual infection, providing the virus with the opportunity for major evolutionary leaps and creating major challenges for diagnosis, treatment, vaccine design, and vaccine trials. Despite the fact that dual infection is common, information on how dual infection impacts on the host's anti-viral humoral immune responses is limited. Studying the impact of dual infection by discordant HIV-1 strains should increase our knowledge of the humoral immune response to diverse viruses. Therefore, the occurrence of dual infection provides a unique opportunity to investigate immune responses to multiple viral antigens and to study whether the host immune response is broadened when challenged with multiple, diverse antigens representing distinct viral subtypes and recombinant viruses. In the West-Central African country of Cameroon, multiple HIV-1 subtypes co-circulate, dual infection is common, and we have identified several individuals dually infected with diverse viruses who have remained asymptomatic and drug-naive for over 3-4 years. The occurrence of dual infections in these drug-naive individuals provides an opportunity to study virus evolution, to examine and compare the effect of infection by single and multiple subtypes on the host immune system in generating neutralizing antibodies, and to study whether such antibodies exhibit differences in their potency and breadth to autologous and/or heterologous viruses. These kinds of studies will shed light on the emergence of new viral subtypes and recombinants and contribute to the design of vaccines that will induce the most potent and broadly neutralizing antibodies to protect against diverse HIV-1 subtypes. Overall, these studies should improve our understanding of the relationship between HV-1 infection, protection, and immunity; and specifically, how HIV evades the immune system and how antiviral immunity impacts viral evolution. We therefore propose studies in: AIM 1: To examine the potency and breadth of neutralization against autologous and heterologous HIV-1 viruses by sequential plasma specimens from either individuals infected with single HIV-1 strains or dually infected with inter- or intra-subtype strains; AIM 2: To study the genetic evolution and emergence of recombinant viruses in the blood of dually (inter-subtype) infected subjects whose serum neutralizing antibodies display different patterns of breadth and potency; and AIM 3: To study the neutralization sensitivity of the recombinant viruses isolated from individuals with inter-subtype dual infections. PUBLIC HEALTH RELEVANCE: The work proposed will study the impact on the humoral immune response and evolution of viruses in HIV-1 dually infected drug naive patients. The study will examine the potency and breadth of neutralizing antibodies in plasma of dually infected patients to autologous and heterologous viruses; and examine the emerging recombinant viruses in these patients and their susceptibility to neutralization. These studies should improve our knowledge on HIV-1 vaccine design and our understanding of the relationship between HV-1 infection, protection, and immunity; and specifically, how HIV evades the immune system and how antiviral immunity impacts viral evolution.

描述（由申请人提供）：在世界中西部非洲等多个 HIV-1 群体和亚型共同传播的地区，双重感染率（两种或多种遗传上不同的 HIV-1 毒株同时或连续感染）很常见，重组病毒也很常见。 HIV-1的一个关键特征是其双重感染后重组的能力，为病毒提供了重大进化飞跃的机会，并给诊断、治疗、疫苗设计和疫苗试验带来了重大挑战。尽管双重感染很常见，但有关双重感染如何影响宿主抗病毒体液免疫反应的信息仍然有限。研究不一致的 HIV-1 毒株双重感染的影响应该会增加我们对不同病毒的体液免疫反应的了解。因此，双重感染的发生提供了一个独特的机会来研究对多种病毒抗原的免疫反应，并研究当用代表不同病毒亚型和重组病毒的多种不同抗原攻击时，宿主免疫反应是否会扩大。在中西部非洲国家喀麦隆，多种 HIV-1 亚型共同传播，双重感染很常见，我们已经确定了数名双重感染多种病毒的人，他们在 3-4 年多的时间里一直保持无症状且未接受药物治疗。这些未曾接受药物治疗的个体中双重感染的发生为研究病毒进化、检查和比较单一和多种亚型感染对宿主免疫系统产生中和抗体的影响以及研究这些抗体是否表现出差异提供了机会其对自体和/或异源病毒的效力和广度。此类研究将揭示新病毒亚型和重组体的出现，并有助于疫苗的设计，从而诱导最有效、最广泛的中和抗体来预防多种 HIV-1 亚型。总体而言，这些研究应该提高我们对 HV-1 感染、保护和免疫之间关系的理解；具体来说，艾滋病毒如何逃避免疫系统以及抗病毒免疫如何影响病毒进化。 因此，我们建议进行以下研究： 目标 1：通过从感染单一 HIV-1 毒株或双重感染亚型间或亚型内毒株的个体中获取连续血浆样本，检查中和自体和异源 HIV-1 病毒的效力和广度;目标 2：研究双重（亚型间）感染受试者血液中重组病毒的遗传进化和出现，这些受试者的血清中和抗体表现出不同的广度和效力模式；目的3：研究从亚型间双重感染个体中分离的重组病毒的中和敏感性。 公共卫生相关性：拟议的工作将研究对 HIV-1 双重感染的初次用药患者的体液免疫反应和病毒进化的影响。该研究将检查双重感染患者血浆中针对自体和异源病毒的中和抗体的效力和广度；并检查这些患者中出现的重组病毒及其对中和的敏感性。这些研究应该提高我们对 HIV-1 疫苗设计的认识，以及对 HV-1 感染、保护和免疫之间关系的理解；具体来说，艾滋病毒如何逃避免疫系统以及抗病毒免疫如何影响病毒进化。