Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria 3000, Australia.
Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia.
Sci Transl Med. 2017 Aug 9;9(402). doi: 10.1126/scitranslmed.aaf1483.
Broadly neutralizing antibodies (BnAbs) protect macaques from cell-free simian/human immunodeficiency virus (SHIV) challenge, but their efficacy against cell-associated SHIV is unclear. Virus in cell-associated format is highly infectious, present in transmission-competent bodily fluids, and potentially capable of evading antibody-mediated neutralization. The PGT121 BnAb, which recognizes an epitope consisting of the V3 loop and envelope glycans, mediates antibody-dependent cellular cytotoxicity and neutralization of cell-to-cell HIV-1 transmission. To evaluate whether a BnAb can prevent infection after cell-associated viral challenge, we infused pigtail macaques with PGT121 or an isotype control and challenged animals 1 hour later intravenously with SHIV-infected splenocytes. All five controls had high viremia 1 week after challenge. Three of six PGT121-infused animals were completely protected, two of six animals had a 1-week delay in onset of high viremia, and one animal had a 7-week delay in onset of viremia. The infused antibody had decayed on average to 2.0 μg/ml by 1 week after infusion and was well below 1 μg/ml (range, <0.1 to 0.8 μg/ml) by 8 weeks. The animals with a 1-week delay before high viremia had relatively lower plasma concentrations of PGT121. Transfer of 22 million peripheral blood mononuclear cells (PBMCs) stored at weeks 1 to 4 from the animal with the 7-week delayed onset of viremia into uninfected macaques did not initiate infection. Our results show that HIV-1-specific neutralizing antibodies have partial efficacy against cell-associated virus exposure in macaques. We conclude that sustaining high concentrations of bioavailable BnAb is important for protecting against cell-associated virus.
广谱中和抗体（BnAbs）可保护猕猴免受无细胞猴/人免疫缺陷病毒（SHIV）的攻击，但它们对细胞相关 SHIV 的疗效尚不清楚。细胞相关形式的病毒具有高度传染性，存在于有传播能力的体液中，并且可能能够逃避抗体介导的中和。PGT121 是一种 BnAb，可识别由 V3 环和包膜糖组成的表位，介导抗体依赖性细胞毒性和中和细胞间 HIV-1 的传播。为了评估 BnAb 是否可以在细胞相关病毒攻击后预防感染，我们将 PGT121 或同种型对照注入长尾猕猴体内，1 小时后通过静脉内用感染 SHIV 的脾细胞对动物进行攻击。所有五个对照在挑战后一周都有高病毒血症。六只接受 PGT121 输注的动物中有三只完全受到保护，六只动物中有两只延迟一周出现高病毒血症，一只动物延迟七周出现病毒血症。输注后的平均抗体衰减到输注后 1 周为 2.0μg/ml，到 8 周时低于 1μg/ml（范围，<0.1 至 0.8μg/ml）。在高病毒血症之前有一周延迟的动物具有相对较低的血浆 PGT121 浓度。将从病毒血症出现 7 周延迟的动物在第 1 至 4 周期间储存的 2200 万个外周血单核细胞（PBMC）转移到未感染的猕猴中，并未引发感染。我们的结果表明，HIV-1 特异性中和抗体对猕猴细胞相关病毒暴露具有部分疗效。我们得出结论，维持高浓度的生物可用 BnAb 对于防止细胞相关病毒至关重要。
