Medical Research Council, UVRI & LSTHM Uganda Research Unit, Plot 51-59, Entebbe, Uganda.
Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, GA 30329, USA.
Viruses. 2022 Feb 7;14(2):334. doi: 10.3390/v14020334.
Detailed characterization of transmitted HIV-1 variants in Uganda is fundamentally important to inform vaccine design, yet studies on the transmitted full-length strains of subtype D viruses are limited. Here, we amplified single genomes and characterized viruses, some of which were previously classified as subtype D by sub-genomic pol sequencing that were transmitted in Uganda between December 2006 to June 2011. Analysis of 5' and 3' half genome sequences showed 73% (19/26) of infections involved single virus transmissions, whereas 27% (7/26) of infections involved multiple variant transmissions based on predictions of a model of random virus evolution. Subtype analysis of inferred transmitted/founder viruses showed a high transmission rate of inter-subtype recombinants (69%, 20/29) involving mainly A1/D, while pure subtype D variants accounted for one-third of infections (31%, 9/29). Recombination patterns included a predominance of subtype D in the / region and a highly recombinogenic envelope gene. The signal peptide-C1 region and gp41 transmembrane domain (Tat2/Rev2 flanking region) were hotspots for A1/D recombination events. Analysis of a panel of 14 transmitted/founder molecular clones showed no difference in replication capacity between subtype D viruses ( = 3) and inter-subtype mosaic recombinants ( = 11). However, individuals infected with high replication capacity viruses had a faster CD4 T cell loss. The high transmission rate of unique inter-subtype recombinants is striking and emphasizes the extraordinary challenge for vaccine design and, in particular, for the highly variable and recombinogenic envelope gene, which is targeted by rational designs aimed to elicit broadly neutralizing antibodies.
详细描述在乌干达传播的 HIV-1 变异体对于疫苗设计至关重要，但对亚型 D 病毒传播全长株的研究有限。在此，我们扩增了单基因组并对病毒进行了特征分析，其中一些病毒之前通过亚基因组 pol 测序被归类为亚型 D，这些病毒于 2006 年 12 月至 2011 年 6 月在乌干达传播。5'和 3'半基因组序列分析表明，73%（19/26）的感染涉及单病毒传播，而 27%（7/26）的感染涉及基于随机病毒进化模型预测的多种变异体传播。推断的传播/原始病毒的亚型分析表明，涉及主要 A1/D 的重组率很高（69%，20/29），而纯亚型 D 变体占感染的三分之一（31%，9/29）。重组模式包括以 D 型为主的 /区和高度重组的包膜基因。信号肽 C1 区和 gp41 跨膜域（Tat2/Rev2 侧翼区）是 A1/D 重组事件的热点。对 14 个传播/原始分子克隆的分析表明，D 型病毒（=3）和异源嵌合重组体（=11）之间在复制能力上没有差异。然而，感染高复制能力病毒的个体的 CD4 T 细胞损失更快。独特的异源重组体的高传播率引人注目，这强调了疫苗设计的巨大挑战，特别是高度可变和重组的包膜基因，这是针对理性设计的目标，旨在引发广泛中和抗体。
