Antibody Responses to a Novel HIV-1 Vaccine Vector

描述（由申请人提供）：HIV-1研究的一个主要目标是开发可诱导高滴度病毒中和抗体（NAb）的疫苗，目的是预防感染。然而，事实证明这一目标很难实现。在缺乏NAb的情况下，疫苗诱导的非中和抗体可能会有一个短暂的机会窗口，以防止广泛的HIV-1感染和CD4+ t细胞的失调。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，这种疫苗依赖于能够清除游离病毒和细胞相关病毒的广泛抗体效应功能。具体而言，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强效fc介导的非中和抗体效应功能的抗体，并有望成为有效的HIV-1疫苗。我们的假设基于以下几个因素：1)非中和抗体介导和调节广泛的抗病毒效应功能，有效清除游离病毒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动物的SIV感染以及在疫苗接种后对致病性SIV或SHIV攻击的保护中发挥有益作用；3)M基因缺失的基于rv的载体诱导高度th1型极化的抗体反应。它们在诱导具有非中和效应功能的抗体方面非常有效，例如抗体依赖性细胞毒性（ADCC）和抗体依赖性细胞病毒抑制（ADCVI）。我们相信，我们可以利用RV-¿M的这一特点，进一步将其开发为一种能够提供非中和抗体介导的保护的HIV-1疫苗。这项探索性资助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HIV（或SIV）抗原的HIV疫苗载体。因此，这项探索性资助的目的是证明表达SIV Env的RV-DM在小鼠中诱导了强有力的fc介导的抗体效应功能，并且它有可能在小鼠和非人灵长类动物中进行额外的（未来的）研究。为实现这些目标，提出了两个目标。目的1旨在构建、恢复和表征表达SIV包膜的新型M基因缺失的rv疫苗。Aim II旨在确认这些新的疫苗载体诱导具有广泛作用的fc介导效应功能的非中和抗体，包括ADCC和ADCVI，它们已被证明可以改善SIV或SHIV保护模型的疫苗接种结果。本提案中描述的实验将确定一种新型疫苗载体的功效，该载体具有诱导强效非中和抗体的潜力，可能有助于清除游离病毒和细胞相关病毒。一旦这一点确定，我们将提出进一步的研究，以推进疫苗在非人类灵长类动物中的试验。

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.