Impact of HLA-B*52:01-Driven Escape Mutations on Viral Replicative Capacity.
Impact of HLA-B*52:01-Driven Escape Mutations on Viral Replicative Capacity.
复制标题
HLA-B*52:01 驱动的逃逸突变对病毒复制能力的影响。
DOI：
10.1128/jvi.02025-19
复制
发表时间：
2020
影响因子：
5.4
通讯作者：
Goulder,Philip
中科院分区：
文献类型：
--
作者：
Tsai,Ming-HanChloe;Singh,Supriya;Adland,Emily;Goulder,Philip
HLA-B*52:01 与防止 HIV 疾病进展密切相关。然而，HLA-B*52:01介导的免疫控制机制尚未得到充分研究。我们在此描述了来自印度德里的大多数 HIV C 分支感染者的队列，其中 HLA-B*52:01 非常流行（表型频率为 22.5%）。与其他队列的研究一致，HLA-B*52:01 的表达与高绝对 CD4 计数相关，因此与 HIV 疾病进展无关。我们在此检查了免疫显性 C 分支 Gag 表位 RMTSPVSI（此处为 RI8；Gag 残基 275 至 282）内 HLA-B*52:01 相关病毒多态性对病毒复制能力 (VRC) 的影响，因为 HLA 介导的 VRC 减少是 HLA 相关 HIV 控制的核心机制。我们在 HLA-B*52:01 阳性个体中观察到 RI8 内 V280T、V280S 和 V280A 变异的频率较高（P =0.0001）。这些变体中的每一种都降低了 C 分支病毒的病毒复制能力，特别是 V280A 变体（在 C 分支共识和印度研究队列共识 p24 Gag 主干中，P<0.0001），这也与供体中显着较高的绝对 CD4 计数相关（中位数为 941.5 个细胞/mm3；P =0.004）。还分析了 HLA-B*52:01 侧翼的第二个 HLA-B*52:01 相关突变 K286R。尽管在 HLA-B*52:01 阳性受试者中选择时通常与 V280X 变体结合使用，但这种突变并没有充当补偿突变体，而是确实进一步降低了 VRC。因此，这些数据与之前的研究一致，表明与 HIV 免疫控制相关的 HLA-B 分子主要针对衣壳蛋白内的保守表位，逃离该表位会导致 VRC 显着减少。 重要性很少有研究探讨印度 HIV 感染者的免疫控制机制，估计印度有 270 万人感染 HIV。我们在此重点关注德里的一个研究队列，该研究队列针对最流行的 HLA-B 等位基因之一 HLA-B*52:01，该等位基因存在于 22.5% 的感染者中。 HLA-B*52:01 在其他队列中一直被证明与防止 HIV 疾病进展相关，但由于该等位基因在北美和欧洲的患病率较低，研究受到限制。在 C 分支感染个体中，我们发现 HLA-B*52:01 是印度群体中表达的所有 HLA-B 等位基因中最具保护性的，并且与最高的绝对 CD4 计数相关。此外，我们还发现 HLA-B*52:01 介导免疫保护的机制至少部分与 HIV 无法逃避 HLA-B*52:01 限制性 p24 Gag 特异性 CD8+T 细胞反应而不导致病毒复制能力显着损失有关。
HLA-B*52:01 is strongly associated with protection against HIV disease progression. However, the mechanisms of HLA-B*52:01-mediated immune control have not been well studied. We here describe a cohort with a majority of HIV C-clade-infected individuals from Delhi, India, where HLA-B*52:01 is highly prevalent (phenotypic frequency, 22.5%). Consistent with studies of other cohorts, expression of HLA-B*52:01 was associated with high absolute CD4 counts and therefore a lack of HIV disease progression. We here examined the impact of HLA-B*52:01-associated viral polymorphisms within the immunodominant C clade Gag epitope RMTSPVSI (here, RI8; Gag residues 275 to 282) on viral replicative capacity (VRC) since HLA-mediated reduction in VRC is a central mechanism implicated in HLA-associated control of HIV. We observed in HLA-B*52:01-positive individuals a higher frequency of V280T, V280S, and V280A variants within RI8 (P =0.0001). Each of these variants reduced viral replicative capacity in C clade viruses, particularly the V280A variant (P <0.0001 in both the C clade consensus and in the Indian study cohort consensus p24 Gag backbone), which was also associated with significantly higher absolute CD4 counts in the donors (median, 941.5 cells/mm3;P =0.004). A second HLA-B*52:01-associated mutation, K286R, flanking HLA-B*52:01-RI8, was also analyzed. Although selected in HLA-B*52:01-positive subjects often in combination with the V280X variants, this mutation did not act as a compensatory mutant but, indeed, further reduced VRC. These data are therefore consistent with previous work showing that HLA-B molecules that are associated with immune control of HIV principally target conserved epitopes within the capsid protein, escape from which results in a significant reduction in VRC.IMPORTANCEFew studies have addressed the mechanisms of immune control in HIV-infected subjects in India, where an estimated 2.7 million people are living with HIV. We focus here on a study cohort in Delhi on one of the most prevalent HLA-B alleles, HLA-B*52:01, present in 22.5% of infected individuals. HLA-B*52:01 has consistently been shown in other cohorts to be associated with protection against HIV disease progression, but studies have been limited by the low prevalence of this allele in North America and Europe. Among the C-clade-infected individuals, we show that HLA-B*52:01 is the most protective of all the HLA-B alleles expressed in the Indian cohort and is associated with the highest absolute CD4 counts. Further, we show that the mechanism by which HLA-B*52:01 mediates immune protection is, at least in part, related to the inability of HIV to evade the HLA-B*52:01-restricted p24 Gag-specific CD8+T-cell response without incurring a significant loss to viral replicative capacity.