Escape and compensation from early HLA-B57-Mediated cytotoxic T-lymphocyte pressure on human immunodeficiency virus type 1 Gag alter capsid interactions with cyclophilin A
Escape and compensation from early HLA-B57-Mediated cytotoxic T-lymphocyte pressure on human immunodeficiency virus type 1 Gag alter capsid interactions with cyclophilin A
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DOI：
10.1128/jvi.01369-07
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发表时间：
2007-11-01
影响因子：
5.4
通讯作者：
Allen, Todd M.
中科院分区：
文献类型：
--
作者：
Brockman, Mark A.;Schneidewind, Arne;Allen, Todd M.
某些组织相容性白细胞抗原（HLA）等位基因与人类免疫缺陷病毒1型（HIV-1）感染个体的临床预后改善有关，但其作用机制尚不明确。研究表明，显性hla - b57限制性Gag表位TW10 （TSTLQEQIGW）的早期CD8(+) t细胞逃逸突变会损害HIV-1在体外的复制能力。我们在此证明衣壳蛋白中的T242N取代与B57（+）进行性疾病个体中亲环蛋白A （CypA）结合环的H-219、I-223和M-228残基上游突变有关。在一个独立的流行病学相关传播对队列中，编码T242N的病毒中这些替换的存在与供者血浆病毒血症显著升高相关，进一步表明这些继发性突变弥补了T242N的复制缺陷。利用NL4-3结构，我们证明了这些CypA环改变在体外部分恢复T242N变异复制的能力。值得注意的是，这些突变还增强了病毒对环孢素A的耐药性，表明补偿病毒对CypA的依赖性降低，而CypA通常是最佳感染性所必需的。因此，TW10的突变允许HIV-1逃避主要的早期CD8(+) t细胞反应，但逃避的好处被衣壳功能缺陷所抵消。这些数据表明，TW10逃逸变异体经历了进入后阻断，部分被cypa结合环的变化所克服，并确定了HIV-1适应度缺陷的机制，该机制可能导致与HLA-B57相关的疾病进展较慢。
Certain histocompatibility leukocyte antigen (HLA) alleles are associated with improved clinical outcomes for individuals infected with human immunodeficiency virus type 1 (HIV-1), but the mechanisms for their effects remain undefined. An early CD8(+) T-cell escape mutation in the dominant HLA-B57-restrieted Gag epitope TW10 (TSTLQEQIGW) has been shown to impair HIV-1 replication capacity in vitro. We demonstrate here that this T242N substitution in the capsid protein is associated with upstream mutations at residues H-219, I-223, and M-228 in the cyclophilin A (CypA)-binding loop in B57(+) individuals with progressive disease. In an independent cohort of epidemiologically linked transmission pairs, the presence of these substitutions in viruses encoding T242N was associated with significantly higher plasma viremia in donors, further suggesting that these secondary mutations compensated for the replication defect of T242N. Using NL4-3 constructs, we illustrate the ability of these CypA loop changes to partially restore replication of the T242N variant in vitro. Notably, these mutations also enhanced viral resistance to the drug cyclosporine A, indicating a reduced dependence of the compensated virus on CypA that is normally essential for optimal infectivity. Therefore, mutations in TW10 allow HIV-1 to evade a dominant early CD8(+) T-cell response, but the benefits of escape are offset by a defect in capsid function. These data suggest that TW10 escape variants undergo a postentry block that is partially overcome by changes in the CypA-binding loop and identify a mechanism for an HIV-1 fitness defect that may contribute to the slower disease progression associated with HLA-B57.