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: 8072166
• 负责人: Phillipe N Nyambi
• 金额: $ 47.63万
• 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/8072166
• 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）：在世界的中西部非洲地区的区域中，多个HIV-1组和亚型共同循环，双重感染的发生率 - 与两个或多个遗传上不同的HIV-1菌株的伴随或顺序感染经常，重组病毒是常见的。 HIV-1的关键特征是它在双重感染后重新组合的能力，为病毒提供了重大进化的机会，并为诊断，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。通过不一致的HIV-1菌株研究双重感染对双重感染的影响，应增加我们对对各种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，可以研究对多种病毒抗原的免疫反应，并研究用代表多种不同的病毒亚型和重组病毒的多种不同的抗原挑战时宿主免疫反应扩大。在西北非洲国家喀麦隆，多个HIV-1亚型共同循环，双重感染很常见，我们已经确定了几个被双向感染的多种病毒感染的人，这些病毒一直无症状和药物含量超过3 - 4年。这些药物个体中双重感染的发生提供了研究病毒进化的机会，以检查和比较单个和多个亚型对宿主免疫系统感染的影响，对宿主免疫系统产生中和抗体的影响，并研究此类抗体是否在其效力和广度上与自动和/或/或异性病毒呈现出差异。这类研究将阐明新的病毒亚型和重组的出现，并有助于设计疫苗，这些疫苗将诱导最有效，最广泛的抗体，以防止各种HIV-1亚型。总体而言，这些研究应提高我们对HV-1感染，保护和免疫之间关系的理解。具体而言，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，我们在以下方面提出了研究：AIM 1：通过顺序的血浆标本对自体和异源HIV-1病毒进行中和的效力和广度，来自感染单个HIV-1菌株的个体或被互可能性菌株或双重感染的个体。目的2：研究重组病毒在双重（囊间）感染受试者中的遗传进化和出现，其血清中和抗体表现出不同的宽度和效能模式；和目标3：研究从患有双重双重感染的个体中分离出的重组病毒的中和敏感性。 公共卫生相关性：提出的工作将研究对HIV-1双感染药物幼稚患者的体液免疫反应和病毒进化的影响。该研究将检查双感染患者对自体和异源病毒的血浆中和抗体的效力和广度。并检查这些患者中新兴的重组病毒及其对中和的敏感性。这些研究应提高我们对HIV-1疫苗设计的知识，以及我们对HV-1感染，保护和免疫之间关系的理解。具体而言，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。