A NOVEL STRATEGY TO INDUCE NEUTRALIZING ANTIBODIES TO HIV

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 迄今为止，诱导对艾滋病毒感染的保护性免疫和防止进展为艾滋病的多种疫苗策略都未获成功。目前的想法是寻找“开箱即用”的方法来克服这一瓶颈，开发有效的疫苗。我们推测，其中一种方法是研究来源于无关病毒的包膜蛋白(GBV-C)作为免疫原的作用，这种免疫原将诱导广泛交叉反应的高滴度中和抗体，从而防止免疫恒河猴在SIV分离株攻击后感染。GBV-C在美国近1%的献血者中流行，但与任何疾病无关。多项研究表明，与单独感染艾滋病毒相比，接触GBV-C和艾滋病毒与更高的CD4+T细胞数量、更低的感染率和更长的生存时间有关。这些事件似乎与针对GBV-C包膜蛋白的抗体的发展有关，并增加了这种抗体可能改变艾滋病毒感染和疾病进展的可能性。最近的研究表明，在体外，针对包膜蛋白的多克隆或单克隆抗体可以中和一大批艾滋病毒分离株和一株新城疫病毒分离株。因此，我们建议对恒河猴进行一项概念验证的初步研究，恒河猴将接种编码包膜蛋白的DNA，然后增加包膜蛋白的剂量。将监测免疫猴子对包膜蛋白的免疫反应，并与未接种疫苗的对照猴子一起接受SIV分离株的攻击，以确定结果。预计这一战略将为开发预防艾滋病毒感染和/或人类疾病进展的有效疫苗提供重要信息。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Multiple vaccine strategies to induce protective immunity against HIV infection and prevention of progression to AIDS, have been unsuccessful as of to date. The current thinking is to look for " outside the box" approaches to overcome this bottle neck in developing an effective vaccine. We hypothesize that one such approach is to investigate the role of an envelope protein derived from an unrelated virus (GBV-C) as an immunogen that will induce broadly cross-reactive high titered neutralizing antibodies that will prevent infection in immunized rhesus monkeys following challenge with a SHIV isolate. GBV-C is prevalent in nearly 1% of blood donors in the US but is not associated with any diseases. Several studies have shown that exposure to GBV-C and HIV is associated with higher CD4+ T cell numbers, lower infection and prolonged survival times when compared with HIV infection alone. Those events appear to correlate with the development of antibodies to envelope protein of GBV-C and raise the possibility that such antibodies may modify HIV infection and disease progression. Recent studies have demonstrated that polyclonal or monoclonal antibodies to the envelope protein neutralized a broad panel of HIV isolates and a SHIV isolate in vitro. Therefore, we propose to conduct a proof -of -concept pilot study using rhesus monkeys that will be vaccinated with DNA coding for the envelope protein followed by booster doses of the envelope protein. The immunized monkeys will be monitored for the development of immune responses to the envelope protein and along with unvaccinated control monkeys will be challenged with a SHIV isolate to determine the outcome. It is anticipated that this strategy will provide important information toward the development of an effective vaccine for the prevention of HIV infection and or disease progression in humans.