Williamson Carolyn, Moodley Chivonne, Magaret Craig A, Giorgi Elena E, Rolland Morgane, Westfall Dylan H, Yssel Anna, Deng Wenjie, Rossenkhan Raabya, Mkhize Nonhlanhla N, Chen Lennie, Zhao Hong, Bhattacharya Tanmoy, Pankow Alec, Murrell Ben, York Talita, Gwashu-Nyangiwe Asanda, Ndabambi Nonkululeko, Thebus Ruwayhida, Cohen Paula, Lambson Bronwen, Kaldine Haajira, Bhebhe Sinethemba, Juraska Michal, Bai Hongjun, deCamp Allan C, Ludwig James, Molitor Cindy, Beaume Nicolas, Matten David, Huang Yunda, Zhang Lily, Reeves Daniel B, Mayer Bryan, Karuna Shelly T, Hural John A, Morris Lynn, Montefiori David, Bumgarner Roger E, Moore Penny L, Edlefsen Paul T, Edupuganti Srilatha, Mgodi Nyaradzo, McElrath M Juliana, Cohen Myron S, Corey Lawrence, Gilbert Peter B, Mullins James I
Institute of Infectious Disease and Molecular Medicine, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu Natal, Durban, South Africa.
bioRxiv. 2025 Jul 10:2025.07.01.659979. doi: 10.1101/2025.07.01.659979.
In the HIV antibody mediated prevention (AMP) trials, the broadly neutralizing antibody VRC01 demonstrated protective efficacy against new diagnoses with susceptible HIV strains. To understand how VRC01 shaped breakthrough infections, we performed deep sequencing on 172 participants in the placebo and treatment arms, generating 63,444 (2.5 kb) and 53,088 (3 kb) sequences. Sequences were classified into transmitted founder lineages (TFLs), and infections with multiple distinct lineages were determined. Multilineage infections were detected in ~38% of participants in both the African (HVTN 703/HPTN 081) and Americas/Europe (HVTN 704/HPTN 085) cohorts, regardless of placebo or treatment group, or cohort. The high levels of multilineage infections could be attributed to minor lineages (<5% abundance) identified in 20% of participants. Infection with VRC01 discordant viruses (IC80s >3-fold different) was observed in 40% of multilineage infections, with a trend toward greater intra-host neutralization differences with increasing VRC01 dose (Jonckheere-Terpstra test, p=0.072). In six VRC01 treated participants who acquired both sensitive (IC80<1μg/ml) and resistant viruses (IC80>3μg/ml), the sensitive lineages declined over time. Recombination was pervasive, observed in 63% of multilineage infections at the time of HIV diagnosis. In one treated participant infected with VRC01 discordant lineages, recombinant viruses preferentially inherited the resistance mutation (binomial p=0.004). In conclusion, our in-depth analysis of breakthrough viruses in the AMP trials revealed a high frequency of multilineage infections, including infections with viruses with different VRC01 sensitivities. This analysis also highlights the role of recombination in shaping intra-host viral evolution and facilitating escape from VRC01.
在HIV抗体介导预防（AMP）试验中，广谱中和抗体VRC01对新诊断出的易感性HIV毒株显示出保护效力。为了解VRC01如何形成突破性感染，我们对安慰剂组和治疗组的172名参与者进行了深度测序，分别生成了63444条（2.5 kb）和53088条（3 kb）序列。序列被分类为传播奠基者谱系（TFLs），并确定了多重不同谱系的感染情况。在非洲（HVTN 703/HPTN 081）和美洲/欧洲（HVTN 704/HPTN 085）队列中，约38%的参与者检测到多重谱系感染，无论其处于安慰剂组还是治疗组，也无论属于哪个队列。多重谱系感染的高比例可归因于20%的参与者中鉴定出的次要谱系（丰度<5%）。在40%的多重谱系感染中观察到感染了与VRC01不一致的病毒（IC80差异>3倍），并且随着VRC01剂量增加，宿主内中和差异有增大的趋势（Jonckheere-Terpstra检验，p = 0.072）。在6名同时感染了敏感病毒（IC80<1μg/ml）和耐药病毒（IC80>3μg/ml）的接受VRC01治疗的参与者中，敏感谱系随时间推移而减少。重组现象普遍存在，在HIV诊断时63%的多重谱系感染中都观察到了重组。在一名感染了与VRC01不一致谱系的接受治疗的参与者中，重组病毒优先继承了耐药突变（二项式检验p = 0.004）。总之，我们对AMP试验中突破性病毒的深入分析揭示了多重谱系感染的高频率，包括感染具有不同VRC01敏感性的病毒。该分析还突出了重组在塑造宿主内病毒进化以及促进病毒从VRC01逃逸方面的作用。
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