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，事实证明这一目标难以实现。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CD 4 + 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HIV疫苗，其依赖于能够清除游离病毒和细胞相关病毒的广泛的抗体效应子功能。具体而言，我们假设表达HIV抗原的基于基质（M）基因缺失的狂犬病病毒的疫苗将诱导具有强效Fc介导的非中和抗体效应子功能的抗体，并且可能有望成为有效的HIV-1疫苗。我们的假设基于几个因素：1）非中和抗体介导和调节广泛的抗病毒效应子功能，其有效地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灵长类动物中的SIV感染和在疫苗接种后针对致病性SIV或SHIV攻击的保护中的有益作用，和3）基于M基因缺失的RV的载体诱导高度Th 1型极化的抗体应答，其高度有效地诱导具有非中和效应子功能的抗体，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，进一步开发它作为一种HIV-1疫苗，能够赋予非中和抗体介导的保护作用。这项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HIV（或SIV）抗原的HIV疫苗载体。因此，该探索性资助的目标是显示表达SIV Env的RV-DM在小鼠中诱导有效的Fc介导的抗体效应子功能，并且其具有在小鼠和非人灵长类动物中进行额外（未来）研究的潜力。为实现这些目标，提出了两个目标。目的I是针对构建、回收和表征表达SIV包膜的新型M基因缺失的RV疫苗。目的II旨在确认这些新的疫苗载体诱导具有广泛作用的Fc介导的效应子功能的非中和抗体，包括ADCC和ADCVI，其已显示在SIV或SHIV保护模型中改善疫苗接种的结果。 本提案中描述的实验将鉴定一种新型疫苗载体的效力，该载体具有诱导可能有助于清除游离病毒和细胞相关病毒的强效非中和抗体的潜力。一旦确定了这一点，我们将提出额外的研究，以推进疫苗在非人灵长类动物中的测试。

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.