Preventing the Hypoxia-Adenosinergic Inhibtion of Anti-HIV Immune Response

人们认为，创新的佐剂可能能够诱导更高滴度的广泛中和抗HIV-1抗体和更好的抗HIV-1 T细胞反应。我们建议探索一种新的机会，通过使用抗腺苷能“辅助佐剂”来提高抗HIV疫苗的有效性。我们的抗腺苷能辅助佐剂是cAMP升高的A2A腺苷受体(A2AR)的合成或天然拮抗剂。我们推测，这些辅助剂将通过阻止细胞外腺苷抑制抗HIV免疫反应来增强抗HIV免疫。这是因为腺苷可能会抑制抗艾滋病毒 T-B-和髓系细胞通过其A2AR发出信号。与项目4一起，我们将使用我们的辅助佐剂进一步提高独特的双功能纳米HIV免疫原(来自项目1、2)的效果，这些免疫原展示天然结构和脂质包膜嵌入的HIV-1 MPER片段，并从颗粒核心释放CD4T细胞表位。新的艾滋病毒免疫原与辅助佐剂一起，有望增加T、B淋巴细胞和髓细胞的贡献，以充分释放其抗艾滋病毒的能力 通过阻止它们被A2AR抑制。 在我们的目标中，我们将确定辅助佐剂是否会防止先天和获得性免疫系统细胞的抑制，以便它们能够充分表达其抗HIV疫苗诱导的活性。我们已经在几种感染性疾病和癌症的体内模型中证明了A2AR拮抗剂对抗病原体和抗肿瘤免疫的强大增强作用。为了支持这里提出的研究的可行性，我们表明，用合成的或天然的a2ar拮抗剂治疗后，显著增加了 在接种了HIV gpl20加佐剂(明矾或Mpla)的小鼠中，抗HIV gpl20IgGi、lgG2a和IgM的水平。这种共佐剂产生gp120特异性抗体数量级增强的方法现在可以应用于诱导广泛中和抗体的免疫原。

It is believed that innovative adjuvants might be capable of inducing higher titers of broadly neutralizing anti-HIV-1 antibodies and better anti-HIV-1 T-cell responses. We propose to explore a novel opportunity to improve the effectiveness of anti-HIV vaccines by using anti-adenosinergic "co-adjuvants". Our antiadenosinergic co-adjuvants are synthetic or natural antagonists of cAMP-elevating A2A adenosine receptor (A2AR). We hypothesize that these co-adjuvants will enhance anti-HIV immunity by preventing the inhibition of anti-HIV immune response by extracellular adenosine. This is because adenosine may inhibit the anti-HIV T- B- and myeloid cells by signaling via their A2AR. Together with Project 4, we will use our co-adjuvants to further improve the effects of unique bifunctional nanoparticle HIV immunogens (from Projects 1, 2) that display the natively-structured and lipid envelope-embedded HIV-1 MPER segment and release CD4 T cell epitopes from the particle core. The novel HIV immunogens, together with co-adjuvants, are expected to increase the contribution of T- and B-lymphocytes and myeloid cells to unleash their full anti-HIV capacities by preventing their inhibition by A2AR. In our aims, we will determine whether co-adjuvants will prevent inhibition of cells of innate and adaptive immune systems so they will fully express their anti-HIV vaccine-induced activities. We have already demonstrated the strong enhancement of anti-pathogen- and anti-tumor immunity by A2AR antagonists in several in vivo models of infectious diseases and cancer. In support ofthe feasibility ofthe studies proposed here, we show that treatment with synthetic or natural A2AR antagonists resulted in significantly increased levels of anti-HIV gpl20 IgGI, lgG2a and IgM in mice that have been vaccinated with HIV gpl20 plus adjuvant (Alum or MPLA). This method of co-adjuvanting to generate an order of magnitude augmentation of gp120-specific antibody can now be applied to immunogens eliciting broadly neutralizing antibodies.