Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
J Virol. 2023 Feb 28;97(2):e0160022. doi: 10.1128/jvi.01600-22. Epub 2023 Feb 9.
Infection by Kaposi sarcoma-associated herpesvirus (KSHV) can cause severe consequences, such as cancers and lymphoproliferative diseases. Whole inactivated viruses (WIV) with chemically destroyed genetic materials have been used as antigens in several licensed vaccines. During KSHV productive replication, virus-like vesicles (VLVs) that lack capsids and viral genomes are generated along with virions. Here, we investigated the immunogenicity of KSHV VLVs produced from a viral mutant that was defective in capsid formation and DNA packaging. Mice immunized with adjuvanted VLVs generated KSHV-specific T cell and antibody responses. Neutralization of KSHV infection by the VLV immune serum was low but was markedly enhanced in the presence of the complement system. Complement-enhanced neutralization and complement deposition on KSHV-infected cells was dependent on antibodies targeting viral open reading frame 4 (ORF4). However, limited complement-mediated enhancement was detected in the sera of a small cohort of KSHV-infected humans which contained few neutralizing antibodies. Therefore, vaccination that induces antibody effector functions can potentially improve infection-induced humoral immunity. Overall, our study highlights a potential benefit of engaging complement-mediated antibody functions in future KSHV vaccine development. KSHV is a virus that can lead to cancer after infection. A vaccine that prevents KSHV infection or transmission would be helpful in preventing the development of these cancers. We investigated KSHV VLV as an immunogen for vaccination. We determined that antibodies targeting the viral protein ORF4 induced by VLV immunization could engage the complement system and neutralize viral infection. However, ORF4-specific antibodies were seldom detected in the sera of KSHV-infected humans. Moreover, these human sera did not potently trigger complement-mediated neutralization, indicating an improvement that immunization can confer. Our study suggests a new antibody-mediated mechanism to control KSHV infection and underscores the benefit of activating the complement system in a future KSHV vaccine.
卡波西肉瘤相关疱疹病毒（KSHV）感染可导致严重后果，如癌症和淋巴组织增生性疾病。化学破坏遗传物质的全灭活病毒（WIV）已被用作几种许可疫苗的抗原。在 KSHV 有性复制过程中，会与病毒颗粒一起产生缺乏衣壳和病毒基因组的病毒样小泡（VLV）。在这里，我们研究了一种在衣壳形成和 DNA 包装缺陷的病毒突变体中产生的 KSHV VLV 的免疫原性。用佐剂处理的 VLV 免疫的小鼠产生了 KSHV 特异性 T 细胞和抗体反应。VLV 免疫血清对 KSHV 感染的中和作用较低，但在补体系统存在下显着增强。补体增强的中和作用和补体在 KSHV 感染细胞上的沉积取决于针对病毒开放阅读框 4（ORF4）的抗体。然而，在一小部分 KSHV 感染的人类血清中检测到有限的补体介导的增强，这些血清中含有很少的中和抗体。因此，诱导抗体效应功能的疫苗接种可能会改善感染诱导的体液免疫。总体而言，我们的研究强调了在未来的 KSHV 疫苗开发中利用补体介导的抗体功能的潜在益处。KSHV 是一种感染后可导致癌症的病毒。预防 KSHV 感染或传播的疫苗将有助于预防这些癌症的发生。我们研究了 KSHV VLV 作为疫苗接种的免疫原。我们确定 VLV 免疫诱导的针对病毒蛋白 ORF4 的抗体可以结合补体系统并中和病毒感染。然而，在 KSHV 感染的人类血清中很少检测到 ORF4 特异性抗体。此外，这些人血清不能有效地触发补体介导的中和作用，表明免疫接种可以带来改善。我们的研究提出了一种新的抗体介导机制来控制 KSHV 感染，并强调了在未来的 KSHV 疫苗中激活补体系统的益处。
