Department of Biomedical Engineering, State University of New York at Buffalo, Buffalo, NY, 14260, USA.
The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450018, Henan, China.
Ann Biomed Eng. 2020 Jul;48(7):1991-2001. doi: 10.1007/s10439-019-02398-8. Epub 2019 Dec 12.
A vaccine that induces broadly neutralizing antibodies (bnAbs) against the human immunodeficiency virus (HIV) would be instrumental in controlling the disease. The membrane proximal external region (MPER) peptide is an appealing antigen candidate since it is conserved and is the target of several human bnAbs, such as 2F5. We previously found that liposomes containing cobalt porphyrin-phospholipid (CoPoP) can bind to a his-tagged MPER peptide, resulting in biomimetic antigen presentation on a lipid bilayer. The present study generated various his-tagged, synthetic MPER fragments, which were bound to liposomes containing CoPoP and a synthetic monophosphoryl lipid A (MPLA) and assessed for immunogenicity in mice. MPER peptides with amino acids stretches originating from the membrane insertion point that were at least 25 amino acids in length, had greater 2F5 reactivity and induced stronger antibody responses, compared to shorter ones. Immunization with the lipid-presented MPER elicited stronger antibody responses compared to Alum and Montanide adjuvants, which could recognize recombinant gp41 and gp140 proteins that contained MPER sequences. The induced antibodies neutralized a tier 1A virus that is sensitive to neutralizing antibodies (W61D(TCLA)0.71), but not another tier 1A nor a tier 2 strain. Co-formulation of the MPER peptide with an unrelated malaria protein antigen (Pfs25) that is effectively adjuvanted with liposomes containing CoPoP and MPLA resulted in elicitation of higher MPER antibody levels, but did not improve neutralization, possibly due to interference with proper peptide presentation in the membrane. Murine hybridomas were generated that produced MPER antibodies, but they were non-neutralizing. These results do not show that bnAbs could be generated with MPER peptides and CoPoP liposomes, but do not rule out this possibility with additional improvements to the approach.
一种能够诱导针对人类免疫缺陷病毒（HIV）的广泛中和抗体（bnAbs）的疫苗对于控制该疾病将是非常重要的。膜近端外部区域（MPER）肽是一种有吸引力的抗原候选物，因为它是保守的，是几种人类 bnAbs 的靶标，如 2F5。我们之前发现，含有钴卟啉磷脂（CoPoP）的脂质体可以与带有 his 标签的 MPER 肽结合，从而在脂质双层上实现仿生抗原呈递。本研究生成了各种带有 his 标签的合成 MPER 片段，这些片段与含有 CoPoP 和合成单磷酰基脂质 A（MPLA）的脂质体结合，并在小鼠中评估其免疫原性。与较短的 MPER 肽相比，具有至少 25 个氨基酸长度的源自膜插入点的氨基酸延伸的 MPER 肽具有更高的 2F5 反应性和诱导更强的抗体反应。与 Alum 和 Montanide 佐剂相比，用脂质呈递的 MPER 免疫可引起更强的抗体反应，这些佐剂可以识别包含 MPER 序列的重组 gp41 和 gp140 蛋白。诱导的抗体中和了对中和抗体敏感的 1A 病毒（W61D（TCLA）0.71），但不能中和另一种 1A 型病毒或 2 型病毒。将 MPER 肽与一种有效的脂质体包封的 CoPoP 和 MPLA 佐剂的无关疟疾蛋白抗原（Pfs25）共同配方化导致更高的 MPER 抗体水平，但没有改善中和作用，可能是由于在膜中适当的肽呈递受到干扰。生成了产生 MPER 抗体的鼠杂交瘤，但它们是非中和性的。这些结果并未表明可以用 MPER 肽和 CoPoP 脂质体产生 bnAbs，但通过对该方法进行额外改进，也不能排除这种可能性。
