Pérez-Saucedo David, Castro-Perea Nancy Vanessa, Ruíz-Cruz Antonio, Bustos-Jaimes Ismael, Viveros-Rogel Mónica, Huerta-Hernández Leonor, Moreno-Fierros Leticia
Mucosal Immunoogy Laboratory, Biomedicine Research Unit, Faculty of Higher Studies Iztacala, National Autonomous University of Mexico. Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla, Estado de México 54090, Mexico.
National Technological of Mexico/Tijuana Technological Institute, Center for Graduate and Research in Chemistry, Postal Box 1166, Tijuana, Baja California 22000, Mexico.
Vaccine. 2025 Jan 25;45:126663. doi: 10.1016/j.vaccine.2024.126663. Epub 2024 Dec 24.
The development of a protective HIV vaccine remains a challenge given the high antigenic diversity and mutational rate of the virus, which leads to viral escape and establishment of reservoirs in the host. Modern antigen design can guide immune responses towards conserved sites, consensus sequences or normally subdominant epitopes, thus enabling the development of broadly neutralizing antibodies and polyfunctional lymphocyte responses. Conventional epitope vaccines can often be impaired by low immunogenicity, a limitation that may be overcome by using a carrier system. In this work, Virus-Like Particles (VLPs) of the B19 human parvovirus were used as a carrier system for multiple HIV-1 epitopes displayed on the surface. Epitopes were selected based on being the binding site of broadly neutralizing antibodies (bnAbs) in patients. Full capsid assembly was confirmed by dynamic light scattering and morphology was confirmed by transmission electron imaging. The resulting chimeric VLPs were termed "VLP-MHIV-A". Antigenicity was confirmed by HIV+ patient sera binding to the chimeric VLP-MHIV-A. To evaluate immunogenicity, female C57bl/6 mice were immunized with the chimeric VLPs either via the intramuscular or subcutaneous route, specific humoral and cellular responses were evaluated, and neutralizing activity was measured in an in vitro reporter cell system. Substantial antibodies against whole-VLPs were induced in serum and vaginal lavages for both immunization routes. Antibody responses against the CD4 binding site, V3 loop and several epitopes of gp41 were detected. Both immunization routes demonstrated neutralizing activity; however, the I.M. route was more effective, showing significant neutralizing activity with up to 50 % inhibition of a tier 1 clade B virus infection. Taken as a whole, these results show that chimeric VLPs are an effective antigen capable of inducing HIV-1 specific antibodies with neutralizing activity.
鉴于HIV病毒具有高度的抗原多样性和突变率，这会导致病毒逃逸并在宿主中建立病毒库，因此开发一种保护性HIV疫苗仍然是一项挑战。现代抗原设计可以引导免疫反应针对保守位点、共有序列或通常为次显性的表位，从而促进广泛中和抗体和多功能淋巴细胞反应的产生。传统的表位疫苗往往因免疫原性低而受到影响，使用载体系统可能会克服这一限制。在这项研究中，B19人细小病毒的病毒样颗粒（VLP）被用作一种载体系统，用于展示表面的多个HIV-1表位。基于患者体内广泛中和抗体（bnAbs）的结合位点来选择表位。通过动态光散射确认了完整衣壳的组装，并通过透射电子成像确认了形态。所得的嵌合VLP被命名为“VLP-MHIV-A”。通过HIV阳性患者血清与嵌合VLP-MHIV-A的结合来确认抗原性。为了评估免疫原性，通过肌肉内或皮下途径用嵌合VLP免疫雌性C57bl/6小鼠，评估特异性体液和细胞反应，并在体外报告细胞系统中测量中和活性。两种免疫途径在血清和阴道灌洗液中均诱导产生了大量针对全VLP的抗体。检测到针对CD4结合位点、V3环和gp41的几个表位的抗体反应。两种免疫途径均显示出中和活性；然而，肌肉内途径更有效，对1级B亚型病毒感染的抑制率高达50%，显示出显著的中和活性。总体而言，这些结果表明嵌合VLP是一种有效的抗原，能够诱导具有中和活性的HIV-1特异性抗体。
