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

描述（由申请人提供）：在世界上的中西部非洲等地区，多个HIV-1组和亚型共同传播，双重感染率-两种或更多种遗传上不同的HIV-1毒株的伴随或顺序感染很常见，重组病毒很常见。HIV-1的一个关键特征是其在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。尽管双重感染是常见的，但关于双重感染如何影响宿主的抗病毒体液免疫应答的信息有限。研究不一致的HIV-1病毒株双重感染的影响应该增加我们对不同病毒的体液免疫应答的知识。因此，双重感染的发生提供了一个独特的机会，以调查免疫应答多种病毒抗原，并研究是否扩大了主机的免疫应答时，挑战与多种不同的抗原代表不同的病毒亚型和重组病毒。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，我们已经确定了几个双重感染不同病毒的人，他们保持无症状和药物初治超过3-4年。在这些药物初治个体中双重感染的发生提供了研究病毒进化的机会，以检查和比较单一和多种亚型感染对宿主免疫系统产生中和抗体的影响，并研究这些抗体是否表现出对自体和/或异源病毒的效力和宽度的差异。这类研究将揭示新的病毒亚型和重组体的出现，并有助于设计疫苗，诱导最有效和广泛中和的抗体，以防止不同的HIV-1亚型。总的来说，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;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。 因此，我们提出了以下研究：目的1：通过来自感染单一HIV-1毒株或双重感染亚型间或亚型内毒株的个体的连续血浆标本，检查对自体和异源HIV-1病毒的中和效力和广度;目的2：研究基因进化和重组病毒在双重免疫系统中的出现，目的3：研究从具有亚型间双重感染的个体分离的重组病毒的中和敏感性。 公共卫生相关性：这项工作将研究对HIV-1双重感染的药物初治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，以及我们对HV-1感染、保护和免疫之间关系的理解;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.