Mboumba Bouassa Ralph-Sydney, Pere Helene, Mossoro-Kpinde Christian Diamant, Roques Pierre, Gody Jean Chrysostome, Moussa Sandrine, Veyer David, Gresenguet Gerard, Charpentier Charlotte, Jenabian Mohammad-Ali, Djoba Siawaya Joel Fleury, Belec Laurent
Laboratoire de Virologie, Hopital Europeen Georges Pompidou, Assistance Publique-Hopitaux de Paris (AP-HP) and Universite de Paris, Paris Sorbonne Cite, Paris, France.
Ecole Doctorale Regionale en Infectiologie Tropicale, Franceville, Gabon.
J Clin Med Res. 2020 Jun;12(6):369-376. doi: 10.14740/jocmr4157. Epub 2020 Jun 4.
Biological monitoring of antiretroviral treatment (ART) in human immunodeficiency virus (HIV)-infected pediatric population remains challenging. The aim of the present study was to assess the long-term HIV-1 genetic diversity in gene in HIV-1-infected children in virological failure under antiretroviral regimen adapted according to the successive World Health Organization (WHO) guidelines for resource-constrained settings.
HIV-1 diversity in gene was assessed in HIV-1-infected children and adolescents born from HIV-infected mothers (median age at follow-up: 13.8 years) in virological failure (VF) despite long-term regimen recommended by the WHO. The numbers of nonsynonymous substitutions per potential nonsynonymous site (dN) and of synonymous substitutions at potential synonymous sites (dS) in HIV-1 gene and the dN/dS ratios were used to estimate the selective pressure on circulating HIV-1.
The immunological responses to ART basically corresponded to: 1) Full therapeutic failure with immunological (I) and virological nonresponses in one-quarter (24.6%) of study children ((I, VF) subgroup); 2) Discordant immunovirological responses with paradoxical high CD4 T cell counts (I) and high HIV-1 RNA load in the remaining cohort patients (75.4%) ((I, VF) subgroup). The mean dS was 1.8-fold higher in (I, VF) than (I, VF) subgroup (25.9 ± 18.4 vs. 14.3 ± 10.8). In the (I, VF) subgroup, the mean dS was 1.6-fold higher than the mean dN. Finally, the mean dN/dS ratio was 2.1-fold lower in (I, VF) than (I, VF) subgroup (0.6 ± 0.3 vs. 1.3 ± 0.7), indicating purifying selection in the immunovirological discordant (I, VF) subgroup and positive selection in the immunovirological failure (I, VF) subgroup.
Children and adolescents in immunovirological therapeutic failure harbor positive selection of HIV-1 strains favoring diversifying in -encoded amino acids. In contrast, children with persistent discordant immunovirological responses show accumulation of mutations and purifying selection in gene sequences, indicating limited genetic evolution and likely suggesting genetic adaptation of viruses to host functional constraints.
对感染人类免疫缺陷病毒（HIV）的儿童群体进行抗逆转录病毒治疗（ART）的生物学监测仍然具有挑战性。本研究的目的是评估在根据世界卫生组织（WHO）针对资源有限环境的 successive 指南调整的抗逆转录病毒治疗方案下，HIV-1 感染且出现病毒学失败的儿童中 基因的长期 HIV-1 基因多样性。
对出生于 HIV 感染母亲的 HIV-1 感染儿童和青少年（随访时的中位年龄：13.8 岁）进行评估，尽管采用了 WHO 推荐的长期治疗方案，但这些儿童仍出现病毒学失败（VF）。HIV-1 基因中每个潜在非同义位点的非同义替换数（dN）和潜在同义位点的同义替换数（dS）以及 dN/dS 比率用于估计对循环 HIV-1 的选择压力。
对 ART 的免疫反应基本对应于：1）四分之一（24.6%）的研究儿童出现完全治疗失败，伴有免疫（I）和病毒学无反应（（I，VF）亚组）；2）其余队列患者（75.4%）出现免疫病毒学反应不一致，表现为矛盾的高 CD4 T 细胞计数（I）和高 HIV-1 RNA 载量（（I，VF）亚组）。（I，VF）亚组的平均 dS 比（I，VF）亚组高 1.8 倍（25.9 ± 18.4 对 14.3 ± 10.8）。在（I，VF）亚组中，平均 dS 比平均 dN 高 1.6 倍。最后，（I，VF）亚组的平均 dN/dS 比率比（I，VF）亚组低 2.1 倍（0.6 ± 0.3 对 1.3 ± 0.7），表明在免疫病毒学不一致（I，VF）亚组中存在纯化选择，而在免疫病毒学失败（I，VF）亚组中存在正选择。
免疫病毒学治疗失败的儿童和青少年中存在 HIV-1 毒株的正选择，有利于编码的氨基酸多样化。相比之下，免疫病毒学反应持续不一致的儿童在 基因序列中显示出突变积累和纯化选择，表明遗传进化有限，可能暗示病毒对宿主功能限制的遗传适应。
