Yin Li, Chang Kai-Fen, Nakamura Kyle J, Kuhn Louise, Aldrovandi Grace M, Goodenow Maureen M
Molecular HIV Host Interaction Section, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, MD, USA.
Illumina Inc., San Diego, CA, USA.
J Clin Pediatr Neonatol. 2021;1(1):9-20. doi: 10.46439/pediatrics.1.003.
Mother-to-child transmission (MTCT) through breastfeeding remains a major source of pediatric HIV-1 infection worldwide. To characterize plasma HIV-1 subtype C populations from infected mothers during pregnancy that related to subsequent breast milk transmission, an exploratory study was designed to apply next generation sequencing and a custom bioinformatics pipeline for HIV-1 gp41 extending from heptad repeat region 2 (HR2) through the membrane proximal external region (MPER) and the membrane spanning domain (MSD). MPER harbors linear and highly conserved epitopes that repeatedly elicits HIV-1 neutralizing antibodies with exceptional breadth. Viral populations during pregnancy from women who transmitted by breastfeeding, compared to those who did not, displayed greater biodiversity, more frequent amino acid polymorphisms, lower hydropathy index and greater positive charge. Viral characteristics were restricted to MPER, failed to extend into flanking HR2 or MSD regions, and were unrelated to predicted neutralization resistance. Findings provide novel parameters to evaluate an association between maternal MPER variants present during gestation and lactogenesis with subsequent transmission outcomes by breastfeeding.
HIV-1 transmission through breastfeeding accounts for 39% of MTCT and continues as a major route of pediatric infection in developing countries where access to interventions for interrupting transmission is limited. Identifying women who are likely to transmit HIV-1 during breastfeeding would focus therapies, such as broad neutralizing HIV monoclonal antibodies (bn-HIV-Abs), during the breastfeeding period to reduce MTCT. Findings from our pilot study identify novel characteristics of gestational viral MPER quasispecies related to transmission outcomes and raise the possibility for predicting MTCT by breastfeeding based on identifying mothers with high-risk viral populations.
在全球范围内，通过母乳喂养进行的母婴传播（MTCT）仍然是儿童感染HIV-1的主要来源。为了表征孕期感染母亲血浆中与后续母乳传播相关的HIV-1 C亚型病毒群体，设计了一项探索性研究，应用下一代测序技术和定制的生物信息学流程，对从七肽重复区域2（HR2）延伸至膜近端外部区域（MPER）和跨膜结构域（MSD）的HIV-1 gp41进行分析。MPER包含线性且高度保守的表位，这些表位能反复引发具有非凡广度的HIV-1中和抗体。与未通过母乳喂养传播病毒的女性相比，通过母乳喂养传播病毒的女性孕期病毒群体表现出更高的生物多样性、更频繁的氨基酸多态性、更低的亲水性指数和更高的正电荷。病毒特征仅限于MPER，未延伸至侧翼的HR2或MSD区域，且与预测的中和抗性无关。这些发现提供了新的参数，用于评估孕期和泌乳期母亲MPER变体与随后母乳喂养传播结果之间的关联。
通过母乳喂养传播的HIV-1占母婴传播的39%，在获得阻断传播干预措施有限的发展中国家，它仍然是儿童感染的主要途径。识别可能在母乳喂养期间传播HIV-1的女性，将有助于在母乳喂养期间集中使用如广泛中和HIV单克隆抗体（bn-HIV-Abs）等疗法，以减少母婴传播。我们的初步研究结果确定了与传播结果相关的孕期病毒MPER准种的新特征，并提高了基于识别具有高风险病毒群体的母亲来预测母乳喂养母婴传播的可能性。
