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

目前，全世界约有3 400万人感染了导致艾滋病的人类免疫缺陷病毒1型（HIV-1），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遏制艾滋病毒的传播。这项研究计划的目标是促进开发有效的艾滋病毒疫苗。以下研究将与一个由美国资助的国际财团进行的艾滋病毒疫苗补充研究产生协同作用，申请人是该财团的一部分。大多数针对其他病毒感染的疫苗通过诱导抗体（Abs）的产生来起作用，抗体是一种特异性结合病毒并阻止感染建立的蛋白质。很可能，诱导能够中和所有HIV流行株的抗体（称为广泛中和（bN）抗体）的疫苗将非常有效。然而，HIV是一种高度可变的病毒，这使得疫苗难以刺激能够识别所有HIV变体的Ab的产生。更重要的是，很少有与艾滋病毒结合的抗体能够中和病毒并阻止感染。最近的研究表明，HIV-1 bNAb对于产生Ab的细胞（B细胞）来说是非常困难的。特化的辅助性T细胞，称为滤泡辅助性T细胞（TFH），为B细胞产生Ab提供帮助。因此，我们假设HIV特异性TFH可能对HIV-1 bNAb的产生非常重要。这项研究的第一个目的是验证这一假设，并比较不同的疫苗接种策略诱导TFH活性的能力。即使是bNAb也不可能在所有情况下都能阻断HIV感染，因此HIV疫苗在感染后引发其他免疫反应来控制病毒复制也很重要。HIV特异性CD 8 T细胞在HIV控制中起重要作用，并且疫苗引发的CD 8 T细胞应答已显示在动物模型中有效地抑制HIV复制。然而，迄今为止在人类疫苗试验中引起的HIV特异性T细胞应答不足以控制病毒复制;此外，HIV能够迅速突变以逃避这些应答。这项研究的第二个目的是开发策略，以引发最佳保护性的HIV特异性CD 8 T细胞应答。我们将研究为什么在自然HIV感染中产生的第一个CD 8 T细胞反应通常只集中在病毒的1-2个位点上（这是有害的，因为病毒在1-2个位点突变比逃避针对许多位点的反应要容易得多），以了解如何通过疫苗接种克服这一点。我们还将研究由牛津开发的一种新的T细胞诱导疫苗引起的CD 8 T细胞反应，该疫苗旨在引起针对HIV不太可能突变的病毒位点的强烈HIV特异性CD 8 T细胞反应。我们将研究这种疫苗诱导的反应的特定方面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（NK）细胞（构成抗感染第一道防线的快速反应细胞）活性的新想法。NK细胞有助于控制HIV，但直到最近，NK细胞才被认为具有B和T细胞的能力，在第二次暴露于特定感染时产生更强的保护性反应，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细胞受体如何识别HIV，以便我们能够设计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.