Antibody Responses to a Novel HIV-1 Vaccine Vector

描述(申请人提供)：HIV-1研究的一个主要目标是开发能够诱导高滴度病毒中和抗体(NAB)的疫苗，以预防感染。然而，事实证明这一目标很难实现。在没有NAB的情况下，疫苗诱导的非中和抗体可能会阻止广泛的HIV-1感染和CD4+T细胞的放松调控，这是一个很短的机会之窗。因此，我们的总体目标是开发一种潜在的新型艾滋病毒疫苗，这种疫苗依赖于广泛的抗体效应器功能，能够清除游离和细胞相关病毒。具体地说，我们假设表达HIV抗原的基质(M)基因缺失狂犬病病毒疫苗将诱导具有Fc介导的非中和抗体效应器功能的抗体，并有望成为有效的HIV-1疫苗。我们的假说基于几个因素：1)非中和抗体介导和调节广泛的抗病毒效应功能，有效清除游离和细胞相关病毒颗粒；2)越来越多的证据支持非中和抗体在控制非人类灵长类SIV感染和预防接种后致病性SIV或SIV攻击方面发挥有益作用；3)M基因缺失的RV载体诱导高度Th1型极化抗体反应，在诱导具有非中和效应功能的抗体方面非常有效，如抗体依赖细胞环状病毒速度(ADCC)和抗体依赖细胞病毒抑制(ADCVI)。我们相信，我们可以利用RV-M的这一特征，将其进一步开发为能够通过非中和抗体介导的保护作用的HIV-1疫苗。这笔探索性赠款是一个多阶段项目的第一阶段，该项目旨在研究RV-M作为表达艾滋病毒(或SIV)抗原的艾滋病毒疫苗载体。因此，这项探索性拨款的目的是证明表达SIV Env的RV-DM在小鼠中诱导强大的Fc介导的抗体效应器功能，并具有在小鼠和非人类灵长类动物中进行进一步(未来)研究的潜力。为了实现这些目标，我们提出了两个目标。目的构建、回收和鉴定表达SIV囊膜的新型M基因缺失轮状病毒疫苗。目的II旨在证实这些新的疫苗载体诱导具有广泛作用的Fc介导的效应器功能的非中和抗体，包括ADCC和ADCVI，已被证明在SIV或SIV保护模型中改善疫苗接种的结果。这项建议中描述的实验将确定一种新的疫苗载体的有效性，该载体具有诱导强大的非中和抗体的潜力，可能有助于清除游离和细胞相关病毒。一旦确定了这一点，我们将提出更多的研究，以推进疫苗在非人类灵长类动物身上的测试。

DESCRIPTION (provided by applicant): A major goal of HIV-1 research is to develop vaccines that induce high titers of virus neutralizing antibodies (NAb) with the goal of preventing infectio. However, this goal is proving difficult to achieve. In the absence of NAb, there is a short window of opportunity where vaccine-induced non-neutralizing antibodies might prevent widespread HIV-1 infection and deregulation of CD4+ T-cells. It is our overall goal therefore to develop a potentially new class of HIV vaccines that rely on a broad range of antibody effector functions capable of clearing both free and cell-associated virus. Specifically, we hypothesize that a matrix (M) gene- deleted rabies virus-based vaccine expressing HIV antigens will induce antibodies with potent Fc-mediated non-neutralizing antibody effector functions and may hold promise as effective HIV-1 vaccines. Our hypothesis is based on several factors: 1) non-neutralizing antibodies mediate and regulate a broad range of anti-viral effector functions that effectively clear both free and cell-associated virus particles, 2) a growing body of evidence supports a beneficial role for non-neutralizing antibodies in the control of SIV infections in non-human primates and in the protection against pathogenic SIV or SHIV challenge after vaccination, and 3) M gene- deleted RV-based vectors induce highly Th1-type polarized antibody responses, which are highly effective at inducing antibodies with non-neutralizing effector functions, such as antibody-dependent cellular cytoxocity (ADCC) and antibody dependent cellular virus inhibition (ADCVI). We believe we can exploit this feature of RV- ¿M to further develop it as an HIV-1 vaccine capable of conferring protection mediated by non-neutralizing antibodies. This exploratory grant is the first phase of a multi-phased project aimed at studying RV-¿M as an HIV vaccine vector expressing HIV (or SIV) antigens. Therefore, the goal of this exploratory grant is to show that RV-DM expressing SIV Env induces potent Fc-mediated antibody effector functions in mice and that it has the potential for additional (future) studies in mice and non-human primates. Two Aims are proposed to achieve these goals. Aim I is directed towards constructing, recovering, and characterizing novel M gene-deleted RV-based vaccines expressing SIV Envelope. Aim II is directed towards confirming these new vaccine vectors induce non-neutralizing antibodies with broadly acting Fc-mediated effector functions, including ADCC and ADCVI, which have been shown to improve the outcome of vaccination in SIV or SHIV models of protection. The experiments described in this proposal will identify the efficacy of a novel vaccine vector with the potential of inducing potent non-neutralizing antibodies that might help to clear free and cell-associated virus. Once this is established, we will propose additional studies to advance the testing of the vaccines in non- human primates.