The HIV-1 epidemic in sub-Saharan Africa is heterogeneous with diverse unevenly distributed subtypes and regional differences in prevalence. Subtype-specific differences in disease progression rate and transmission efficiency have been reported, but the underlying biological mechanisms have not been fully characterized. Here, we tested the hypothesis that the subtypes prevalent in the East Africa, where adult prevalence rate is higher, have lower viral replication capacity (VRC) than their West African counterparts where adult prevalence rates are lower. Gag-protease sequencing was performed on 213 and 160 antiretroviral-naïve chronically infected participants from West and East Africa respectively and bioinformatic tools were used to infer subtypes and recombination patterns. VRC of patient-derived gag-protease chimeric viruses from West (n = 178) and East (n = 114) Africa were determined using a green fluorescent protein reporter-based cell assay. Subtype and regional differences in VRC and amino acid variants impacting VRC were identified by statistical methods. CRF02_AG (65%, n = 139), other recombinants (14%, n = 30) and pure subtypes (21%, n = 44) were identified in West Africa. Subtypes A1 (64%, n = 103), D (22%, n = 35), or recombinants (14%, n = 22) were identified in East Africa. Viruses from West Africa had significantly higher VRC compared to those from East Africa (p < 0.0001), with subtype-specific differences found among strains within West and East Africa (p < 0.0001). Recombination patterns showed a preference for subtypes D, G or J rather than subtype A in the p6 region of gag, with evidence that subtype-specific differences in this region impact VRC. Furthermore, the Gag A83V polymorphism was associated with reduced VRC in CRF02_AG. HLA-A*23:01 (p = 0.0014) and HLA-C*07:01 (p = 0.002) were associated with lower VRC in subtype A infected individuals from East Africa. Although prevalent viruses from West Africa displayed higher VRC than those from East Africa consistent with the hypothesis that lower VRC is associated with higher population prevalence, the predominant CRF02_AG strain in West Africa displayed higher VRC than other prevalent strains suggesting that VRC alone does not explain population prevalence. The study identified viral and host genetic determinants of virus replication capacity for HIV-1 CRF02_AG and subtype A respectively, which may have relevance for vaccine strategies.

中文翻译：

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东非和西非 HIV-1 分离株 Gag 蛋白酶复制能力的亚型特异性差异


撒哈拉以南非洲地区的 HIV-1 疫情具有异质性，亚型分布不均匀，患病率存在​​区域差异。疾病进展率和传播效率方面的亚型特异性差异已有报道，但潜在的生物学机制尚未得到充分表征。在这里，我们测试了这样的假设：在成人患病率较高的东非流行的亚型，其病毒复制能力（VRC）低于成人患病率较低的西非亚型。分别对来自西非和东非的 213 名和 160 名未接受过抗逆转录病毒治疗的慢性感染参与者进行了 Gag 蛋白酶测序，并使用生物信息学工具推断亚型和重组模式。使用基于绿色荧光蛋白报告基因的细胞测定法测定了来自西非 (n = 178) 和东非 (n = 114) 的患者来源的 gag 蛋白酶嵌合病毒的 VRC。通过统计方法确定了 VRC 的亚型和区域差异以及影响 VRC 的氨基酸变异。在西非发现了 CRF02_AG（65%，n = 139）、其他重组体（14%，n = 30）和纯亚型（21%，n = 44）。在东非发现了 A1 亚型（64%，n = 103）、D 亚型（22%，n = 35）或重组亚型（14%，n = 22）。与东非病毒相比，西非病毒的 VRC 显着更高 (p < 0.0001)，西非和东非病毒株之间存在亚型特异性差异 (p < 0.0001)。重组模式显示，在 gag 的 p6 区域中，更倾向于 D、G 或 J 亚型，而不是 A 亚型，有证据表明该区域的亚型特异性差异会影响 VRC。此外，Gag A83V 多态性与 CRF02_AG 中 VRC 减少相关。 HLA-A*23:01 (p = 0.0014) 和 HLA-C*07:01 (p = 0.002) 与东非 A 亚型感染者较低的 VRC 相关。尽管西非流行病毒表现出比东非流行病毒更高的 VRC，这与较低 VRC 与较高人群流行率相关的假设相一致，但西非的主要 CRF02_AG 毒株表现出比其他流行毒株更高的 VRC，表明 VRC 本身并不能解释人群流行率。该研究分别确定了 HIV-1 CRF02_AG 和 A 亚型病毒复制能力的病毒和宿主遗传决定因素，这可能与疫苗策略相关。