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

描述(由申请人提供)：在世界上多个艾滋病毒-1组和亚型共同传播的西非和中非地区，双重感染率--与两个或更多基因不同的艾滋病毒-1毒株相伴或相继感染是频繁的，重组病毒很常见。HIV-1的一个关键特征是在双重感染后进行重组的能力，这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，但关于双重感染如何影响宿主的抗病毒体液免疫反应的信息有限。研究不协调的HIV-1毒株双重感染的影响将增加我们对不同病毒的体液免疫反应的了解。因此，双重感染的发生为研究对多种病毒抗原的免疫反应提供了独特的机会，并研究了当代表不同病毒亚型和重组病毒的多种不同抗原攻击时，宿主免疫反应是否被扩大。在西非-中非国家喀麦隆，多种HIV-1亚型共同传播，双重感染很常见，我们发现几个人双重感染不同的病毒，他们3-4年多来一直没有症状和吸毒。在这些药物初学者身上发生双重感染，为研究病毒的进化，检查和比较单一亚型和多亚型感染对宿主免疫系统产生中和抗体的影响，以及研究这些抗体对自体和/或异源病毒的效力和广度是否存在差异提供了机会。这类研究将揭示新的病毒亚型和重组体的出现，并有助于疫苗的设计，这些疫苗将诱导最有效和最广泛的中和抗体，以保护不同的HIV-1亚型。总体而言，这些研究应该会提高我们对HV-1感染、保护和免疫之间的关系的理解；特别是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：目的1：检测单个HIV-1毒株感染个体以及亚型间和亚型内双重感染个体的连续血浆标本对自体和异源HIV-1病毒的中和效力和广度；目的2：研究血清中和抗体呈现不同广度和效力模式的双重(亚型间)感染者血液中重组病毒的遗传进化和出现；以及目的3：研究从亚型间双重感染个体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双重感染药物初治患者的体液免疫反应和病毒进化的影响。这项研究将检测双重感染患者血浆中对自体和异源病毒的中和抗体的效力和广度；并检测这些患者中出现的重组病毒及其对中和的敏感性。这些研究将提高我们对HIV-1疫苗设计的了解，以及我们对HV-1感染、保护和免疫之间的关系的理解，特别是HIV如何逃避免疫系统以及抗病毒免疫如何影响病毒进化。

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.