Design of HIV vaccines that stimulate T cell and NK cell immunity

目前全球约有3400万人感染了人类免疫缺陷病毒1型(HIV-1)，这是导致艾滋病的病毒，2010年有180万人死于艾滋病。尽管在治疗和预防艾滋病毒感染方面取得了进展，但2010年仍有约270万人新感染艾滋病毒。因此，迫切需要一种疫苗来对抗艾滋病毒的传播。这项研究计划的目标是为开发有效的艾滋病毒疫苗作出贡献。以下研究将与一个由美国资助的国际财团正在进行的补充性艾滋病毒疫苗研究相配合，申请者是该财团的一部分。开发有效的艾滋病毒疫苗是非常具有挑战性的。大多数其他病毒感染的疫苗是通过诱导抗体(Abs)的产生来发挥作用的，抗体是一种与病毒特异结合的蛋白质，可以阻止感染的建立。一种诱导能够中和所有正在传播的艾滋病毒毒株的抗体(称为广义中和抗体)的疫苗很可能是非常有效的。然而，艾滋病毒是一种高度可变的病毒，这使得疫苗很难刺激产生能够识别所有艾滋病毒变体的抗体。更重要的是，与艾滋病毒结合的抗体中很少有真正能够中和病毒和阻止感染的。最近的研究表明，HIV-1的bNAbs对于产生抗体的细胞(B细胞)来说非常困难。特殊的辅助性T细胞，称为滤泡辅助性T细胞(TFH)，为B细胞产生抗体提供帮助。我们推测，HIV特异性的TFH可能因此对HIV-1bNAb的产生非常重要。这项拟议研究的第一个目标将是检验这一假设，并比较不同疫苗接种策略诱导TFH活性的能力。即使bNAbs也不可能在所有情况下都能阻止HIV感染，因此HIV疫苗激发其他免疫反应来控制感染后的病毒复制也是重要的。HIV特异性CD8T细胞在HIV控制中发挥着重要作用，疫苗诱导的CD8T细胞反应在动物模型中被证明有效地抑制了HIV的复制。然而，迄今为止在人类疫苗试验中引起的艾滋病毒特异性T细胞反应还不足以控制病毒复制；此外，艾滋病毒能够迅速变异以逃避这些反应。这项拟议研究的第二个目标将是开发策略，以诱导最佳保护性HIV特异性CD8 T细胞反应。我们将研究为什么在自然感染HIV中产生的第一批CD8 T细胞反应通常只集中在病毒的1-2个部位(这是有害的，因为病毒在1-2个部位变异比逃脱针对多个部位的反应要容易得多)，以了解如何通过接种疫苗来克服这一点。我们还将研究牛津大学开发的一种新的T细胞诱导疫苗引发的CD8 T细胞反应，该疫苗旨在诱导针对HIV病毒中不太可能发生突变的部位的强大的HIV特异性CD8 T细胞反应。我们将研究这种疫苗诱导的特定方面的反应如何增强或降低疫苗效力，如果需要，将根据我们的结果设计改进的T细胞疫苗。我们的第三个目标是探索在HIV疫苗设计中利用自然杀伤细胞(NK细胞)的活性的新想法。NK细胞是构成对抗感染的第一道防线的快速反应细胞。NK细胞有助于控制HIV，但直到最近，NK细胞还没有被认为具有B细胞和T细胞的能力，即在二次接触特定感染时产生更具保护性的反应，这构成了疫苗接种的基础。我们计划研究疫苗是否可以诱导人类NK细胞反应的长期变化。我们还将分析NK细胞受体是如何识别HIV的，这样我们就可以设计NK刺激疫苗来对抗HIV感染。

Around 34 million people worldwide are currently infected with human immunodeficiency virus type 1 (HIV-1), the virus that causes AIDS, and 1.8 million people died of AIDS in 2010. Despite advances in the treatment and prevention of HIV infection, ~2.7 million people became newly-infected with HIV in 2010. A vaccine is therefore urgently needed to combat HIV spread. The goal of this research programme is to contribute to the development of an effective HIV vaccine. The studies below will synergise with complementary HIV vaccine research being carried out by a US-funded international consortium of which the applicants are part.Development of effective HIV vaccines is very challenging. Most vaccines for other virus infections work by inducing the production of antibodies (Abs), proteins that bind specifically to the virus and block the establishment of infection. It is likely that a vaccine that induced Abs capable of neutralising all the circulating strains of HIV (termed broadly-neutralising (bN)Abs ) would be very effective. However HIV is a highly variable virus, which makes it difficult for vaccines to stimulate the production of Abs capable of recognising all HIV variants. Even more importantly, very few of the Abs that bind to HIV are actually able to neutralise the virus and block infection. Recent studies have shown that HIV-1 bNAbs are very difficult for Ab-producing cells (B cells) to make. Specialised helper T cells, termed follicular helper T cells (TFH), provide help to B cells for Ab production. We hypothesise that HIV-specific TFH may therefore be very important for the generation of HIV-1 bNAbs. The first aim of the proposed research will be to test this hypothesis, and to compare the ability of different vaccination strategies to induce TFH activity.Even bNAbs are not likely to be able to block HIV infection in all cases, so it is also important for HIV vaccines to elicit other immune responses that can control virus replication after infection. HIV-specific CD8 T cells play an important role in HIV control, and vaccine-elicited CD8 T cell responses have been shown to contain HIV replication efficaciously in animal models. However the HIV-specific T cell responses elicited in human vaccine trials to date have not been adequate to control virus replication; furthermore HIV was rapidly able to mutate to escape from these responses. The second aim of the proposed research will be to develop strategies to elicit optimally-protective HIV-specific CD8 T cell responses. We will study why the first CD8 T cell responses made in natural HIV infection are often focused on just 1-2 sites in the virus (which is detrimental, as it is much easier for the virus to mutate at 1-2 sites than to escape from responses targeted to many sites), to understand how this can be overcome by vaccination. We will also study the CD8 T cell responses elicited by a new T cell-inducing vaccine developed in Oxford, which has been designed to elicit strong HIV-specific CD8 T cell responses targeted to sites in the virus where HIV is less likely to be able to mutate. We will investigate how specific aspects of the responses induced by this vaccine may enhance or reduce vaccine efficacy, and if required, will design improved T cell vaccines based on our results. Our third aim will be to explore the novel idea of harnessing the activity of natural killer (NK) cells (rapidly-responding cells that form part of the first line of defence against infection) in HIV vaccine design. NK cells contribute to HIV control, but until recently NK cells were not thought to share the ability of B and T cells to mount a more protective response on second exposure to a particular infection, which forms the basis of vaccination. We plan to study whether vaccines can induce long-lasting changes in NK cell responses in humans. We will also analyse how NK cell receptors recognise HIV, so that we can design NK-stimulatory vaccines to combat HIV infection.