Global Health and Tropical Medicine-GHTM, Instituto de Higiene e Medicina Tropical-IHMT, Universidade Nova de Lisboa-UNL, 1349-008, Lisboa, Portugal.
Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Lisboa, 1649-003, Lisboa, Portugal.
Sci Rep. 2021 Apr 26;11(1):8993. doi: 10.1038/s41598-021-88274-9.
The ectodomain of gp41 is the target of potent binding and neutralizing antibodies (NAbs) and is being explored in new strategies for antibody-based HIV vaccines. Previous studies have suggested that the W164A-3S (3S) and EC26-2A4 (EC26) peptides located in the gp41 ectodomain may be potential HIV vaccine candidates. We assessed 3S- and EC26-specific binding antibody responses and related neutralizing activity in a large panel of chronic HIV-1-infected Portuguese individuals on ART. A similar proportion of participants had antibodies binding to 3S (9.6%) and EC26 (9.9%) peptides but the level of reactivity against 3S was significantly higher compared to EC26, except in the rare patients with double peptide reactivity. The higher antigenicity of 3S was unrelated with disease stage, as assessed by CD4 T cell counts, but it was directly related with plasma viral load. Most patients that were tested (89.9%, N = 268) showed tier 1 neutralizing activity, the potency being inversely associated with plasma viral load. In the subset of patients that were tested for neutralization of tier 2 isolates, neutralization breadth was inversely correlated with plasma viral load and directly correlated with CD4 T cell counts. These results are consistent with a role for neutralizing antibodies in controlling viral replication and preventing the decline of CD4 T lymphocytes. Importantly, in patients with 3S-specific antibodies, neutralizing titers were inversely correlated with viral RNA levels and proviral DNA levels. Moreover, patients with 3S and/or EC26-specific antibodies showed a 1.9-fold higher tier 2 neutralization score than patients without antibodies suggesting that 3S and/or EC26-specific antibodies contribute to neutralization breadth and potency in HIV-1 infected patients. Overall, these results suggest that antibodies targeting the S3 and EC26 epitopes may contribute to reduce viral burden and provide further support for the inclusion of 3S and EC26 epitopes in HIV-1 vaccine candidates.
gp41 的外结构域是强效结合和中和抗体（NAb）的靶标，目前正在探索新的基于抗体的 HIV 疫苗策略。先前的研究表明，gp41 外结构域中的 W164A-3S（3S）和 EC26-2A4（EC26）肽可能是潜在的 HIV 疫苗候选物。我们评估了在接受 ART 的大量慢性 HIV-1 感染葡萄牙个体中，3S-和 EC26 特异性结合抗体反应和相关中和活性。具有针对 3S（9.6%）和 EC26（9.9%）肽结合抗体的参与者比例相似，但针对 3S 的反应水平明显高于 EC26，除了极少数具有双重肽反应的患者。3S 的较高抗原性与疾病阶段无关，如 CD4 T 细胞计数评估所示，但与血浆病毒载量直接相关。大多数接受测试的患者（89.9%，N=268）表现出 1 级中和活性，效力与血浆病毒载量呈反比。在接受 2 级分离株中和测试的患者亚组中，中和广度与血浆病毒载量呈反比，与 CD4 T 细胞计数呈直接相关。这些结果与中和抗体在控制病毒复制和防止 CD4 T 淋巴细胞下降方面的作用一致。重要的是，在具有 3S 特异性抗体的患者中，中和滴度与病毒 RNA 水平和前病毒 DNA 水平呈反比。此外，具有 3S 和/或 EC26 特异性抗体的患者比没有抗体的患者具有更高的 2 级中和评分，这表明 3S 和/或 EC26 特异性抗体有助于 HIV-1 感染患者的中和广度和效力。总的来说，这些结果表明，针对 S3 和 EC26 表位的抗体可能有助于降低病毒负担，并为将 3S 和 EC26 表位纳入 HIV-1 疫苗候选物提供进一步支持。
