Defining Immune Deficits in HIV-1 Infected Women

描述（由申请人提供）：艾滋病的流行仍在继续，有效疫苗的前景为艾滋病预防提供了最大的希望。我们研制保护性疫苗的努力受到阻碍，因为我们仍然不了解免疫力与HIV-1的相关性。正在进行的疫苗试验有望深入了解在慢性感染期间参与控制HIV-1复制的免疫反应是否也可以在介导保护免受HIV-1新感染方面发挥作用。最近关于HIV-1重复感染（也称为再感染，定义为在第一种病毒已经在个体中建立之后被第二种病毒感染）的报道表明，在自然感染期间产生的免疫应答不 必然会产生保护性免疫。因此，确定潜在的免疫缺陷， 个体对于疫苗设计很重要。我们的实验室最近发现了几例HIV-1病例 肯尼亚蒙巴萨一群高危妇女中的双重感染。我们假设， 对HIV-1的体液免疫和细胞免疫都有助于第二种病毒株建立 感染该提案的目的是描述双重感染者对HIV-1的体液和细胞免疫反应，并将这些反应与未被双重感染的女性进行比较。为了分析体液免疫应答，我们将首先从最初感染和重复感染的菌株产生一组全长功能性包膜克隆。我们将使用这些包膜来开发一组病毒，我们可以评估双重感染妇女和未显示双重感染证据的妇女中中和抗体反应的效力和广度。我们的目的是确定相关的细胞免疫，使用多参数流式细胞术和多重细胞因子评估后，刺激外周血单核细胞与HIV-1和非HIV-1抗原。我们将评估是否有赤字或变化，细胞因子的生产，细胞溶解，和CD 4+和CD 8 + T细胞在重叠感染的妇女之间的增殖能力。对双重感染妇女的体液和细胞免疫反应的分析将有助于确定对艾滋病毒的保护性免疫和失败免疫的相关性;这些进展将提供关键的见解，以纳入未来的疫苗设计。

DESCRIPTION (provided by applicant): The AIDS pandemic continues unchecked, and the prospect of an effective vaccine provides the best hope for HIV prevention. Our efforts to develop a protective vaccine have been hampered by the fact that we still do not understand correlates of immunity to HIV-1. Ongoing vaccine trials promise to provide insight into whether the immune responses that are involved in controlling HIV-1 replication during chronic infection can also play a role in mediating protection from new infection with HIV-1. Recent reports of HIV-1 superinfection (also called re-infection, defined as infection by a second virus after the first virus is already established in the individual), suggest that the immune responses generated during natural infection do not necessarily induce protective immunity. Thus, identifying potential immune deficits in superinfected individuals will be important for vaccine design. Our lab has recently identified several cases of HIV-1 superinfection among a cohort of high-risk women in Mombasa, Kenya. We hypothesize that deficits in both humoral and cellular immunity to HIV-1 contribute to the ability of a second viral strain to establish infection. The aims of this proposal are to characterize the humoral and cellular immune responses to HIV-1 in superinfected individuals, and to compare these responses to those of women who have not become superinfected. To analyze the humoral immune responses, we will first generate a panel of full length, functional envelope clones from initially infecting and superinfecting strains. We will use these envelopes to develop a panel of viruses with which we can assess the potency and the breadth of the neutralizing antibody responses in superinfected women and in women who do not show evidence of superinfection. We aim to identify correlates of cellular immunity using multiparameter flow cytometry and multiplex cytokine assessment following stimulation of peripheral blood mononuclear cells with HIV-1 and non-HIV-1 antigens. We will assess whether there are deficits or changes in cytokine production, cytolysis, and proliferative capacity among CD4+ and CD8+ T cells in superinfected women. Analyses of the humoral and cellular immune responses of women who have become superinfected will aid in defining correlates of both protective and failed immunity to HIV; such advances will provide key insights to incorporate into future vaccine design.