Table_11_Exome Sequencing Reveals a Putative Role for HLA-C*03:02 in Control of HIV-1 in African Pediatric Populations.XLSX

Human leucocyte antigen (HLA) class I molecules present endogenously processed antigens to T-cells and have been linked to differences in HIV-1 disease progression. HLA allelotypes show considerable geographical and inter-individual variation, as does the rate of progression of HIV-1 disease, with long-term non-progression (LTNP) of disease having most evidence of an underlying genetic contribution. However, most genetic analyses of LTNP have occurred in adults of European ancestry, limiting the potential transferability of observed associations to diverse populations who carry the burden of disease. This is particularly true of HIV-1 infected children. Here, using exome sequencing (ES) to infer HLA allelotypes, we determine associations with HIV-1 LTNP in two diverse African pediatric populations. We performed a case-control association study of 394 LTNPs and 420 rapid progressors retrospectively identified from electronic medical records of pediatric HIV-1 populations in Uganda and Botswana. We utilized high-depth ES to perform high-resolution HLA allelotyping and assessed evidence of association between HLA class I alleles and LTNP. Sixteen HLA alleles and haplotypes had significantly different frequencies between Uganda and Botswana, with allelic differences being more prominent in HLA-A compared to HLA-B and C allelotypes. Three HLA allelotypes showed association with LTNP, including a novel association in HLA-C (HLA-B∗57:03, aOR 3.21, Pc = 0.0259; B∗58:01, aOR 1.89, Pc = 0.033; C∗03:02, aOR 4.74, Pc = 0.033). Together, these alleles convey an estimated population attributable risk (PAR) of non-progression of 16.5%. We also observed novel haplotype associations with HLA-B∗57:03-C∗07:01 (aOR 5.40, Pc = 0.025) and HLA-B∗58:01-C∗03:02 (aOR 4.88, Pc = 0.011) with a PAR of 9.8%, as well as a previously unreported independent additive effect and heterozygote advantage of HLA-C∗03:02 with B∗58:01 (aOR 4.15, Pc = 0.005) that appears to limit disease progression, despite weak LD (r2 = 0.18) between these alleles. These associations remained irrespective of gender or country. In one of the largest studies of HIV in Africa, we find evidence of a protective effect of canonical HLA-B alleles and a novel HLA-C association that appears to augment existing HIV-1 control alleles in pediatric populations. Our findings outline the value of using multi-ethnic populations in genetic studies and offer a novel HIV-1 association of relevance to ongoing vaccine studies.

人类白细胞抗原（Human leucocyte antigen, HLA）I类分子可将内源性加工抗原呈递给T细胞，且与HIV-1疾病进展速率差异密切相关。HLA等位基因亚型存在显著的地理与个体间差异，HIV-1疾病进展速率亦是如此，其中长期不进展者（long-term non-progression, LTNP）的疾病进程有充分证据表明其背后存在遗传贡献。然而，绝大多数针对LTNP的遗传分析均以欧洲血统成年人群为研究对象，这使得所观察到的关联结果难以推广至承担疾病负担的其他多样化人群，针对HIV-1感染儿童的相关研究更是如此。
本研究通过外显子组测序（exome sequencing, ES）推断HLA等位基因亚型，在两个多样化的非洲儿童人群中分析其与HIV-1 LTNP的关联。我们对从乌干达和博茨瓦纳儿童HIV-1人群电子病历中回顾性筛选出的394名LTNP患者与420名快速进展者开展了病例对照关联研究。借助高深度外显子组测序进行高分辨率HLA等位基因分型，我们评估了HLA I类等位基因与LTNP之间的关联证据。
乌干达与博茨瓦纳人群中共存在16个HLA等位基因及单倍型的频率存在显著差异，其中HLA-A位点的等位基因差异相较于HLA-B与HLA-C位点更为突出。共有3种HLA等位基因亚型与LTNP存在显著关联，包括一项新发现的HLA-C位点关联：HLA-B*57:03（调整后比值比[aOR]=3.21，Pc=0.0259）、B*58:01（aOR=1.89，Pc=0.033）以及C*03:02（aOR=4.74，Pc=0.033）。上述等位基因合计估计可带来16.5%的疾病不进展人群归因风险（population attributable risk, PAR）。
我们还发现了新的HLA单倍型关联：HLA-B*57:03-C*07:01（aOR=5.40，Pc=0.025）与HLA-B*58:01-C*03:02（aOR=4.88，Pc=0.011），二者的人群归因风险合计为9.8%。此外，我们观察到此前未被报道的HLA-C*03:02与B*58:01存在独立加性效应及杂合子优势（aOR=4.15，Pc=0.005），尽管这两个等位基因间的连锁不平衡（linkage disequilibrium, LD）程度较弱（r²=0.18），但该效应似乎可延缓疾病进展。上述关联不受性别或国家的影响。
作为非洲地区规模最大的HIV研究之一，本研究发现经典HLA-B等位基因具有保护效应，且新发现的HLA-C位点关联可增强儿童人群中现有的HIV-1调控等位基因的作用。我们的研究结果阐明了在遗传研究中使用多民族人群的价值，并为当前正在进行的疫苗研究提供了一项新的HIV-1关联靶点。