撒哈拉以南非洲的HIV-1流行病具有异质性,亚型分布不均,流行率存在区域差异。已经报道了疾病进展率和传播效率的亚型特异性差异,但是潜在的生物学机制还没有被完全描述。这里,我们检验了东非普遍存在的亚型的假设,成人患病率较高的地方,病毒复制能力(VRC)低于成人患病率较低的西非同行。
分别对来自西非和东非的213和160名抗逆转录病毒初治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来推断亚型和重组模式。使用基于绿色荧光蛋白报告子的细胞测定法确定来自西部(n=178)和东部(n=114)非洲的患者来源的gag-蛋白酶嵌合病毒的VRC。通过统计学方法鉴定VRC和影响VRC的氨基酸变体的亚型和区域差异。CRF02_AG(65%,n=139),其他重组体(14%,n=30)和纯亚型(21%,n=44)在西非确定。A1亚型(64%,n=103),D(22%,n=35),或重组体(14%,n=22)在东非确定。来自西非的病毒的VRC明显高于来自东非的病毒(p<0.0001),在西非和东非的菌株之间发现了亚型特异性差异(p<0.0001)。重组模式显示出对D亚型的偏好,gagp6区域的G或J而不是亚型A,有证据表明该区域亚型特异性差异会影响VRC。此外,GagA83V多态性与CRF02_AG中VRC降低有关。HLA-A*23:01(p=0.0014)和HLA-C*07:01(p=0.002)与来自东非的A型感染个体的较低VRC相关。
尽管来自西非的流行病毒的VRC高于来自东非的流行病毒,这与以下假设一致:较低的VRC与较高的人群流行率有关,西非主要的CRF02_AG毒株的VRC高于其他流行毒株,提示仅VRC并不能解释人口流行.该研究分别确定了HIV-1CRF02_AG和A型亚型病毒复制能力的病毒和宿主遗传决定因素,这可能与疫苗策略有关。
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.