HIV-1 replication fitness of HLA-B*57/58:01 CTL escape variants is restored by the accumulation of compensatory mutations in gag.
HIV-1 replication fitness of HLA-B*57/58:01 CTL escape variants is restored by the accumulation of compensatory mutations in gag.
复制标题
DOI：
10.1371/journal.pone.0081235
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kootstra NA
中科院分区：
文献类型：
--
作者：
Gijsbers EF;Feenstra KA;van Nuenen AC;Navis M;Heringa J;Schuitemaker H;Kootstra NA
HLA-B*57 和密切相关的 HLA-B*58:01 的表达与 HIV-1 感染后延长生存期相关。然而，HLA-B*57/58:01 患者的病程存在很大差异。受这些 HLA 等位基因限制的 CTL 表位中的逃逸突变会产生适应性成本，特别是 Gag 中 TW10 CTL 表位中的 T242N 突变已被证明会降低病毒复制能力。该 CTL 表位内或侧翼的额外突变可以部分恢复 CTL 逃逸变体的复制适应性。对 5 个 HLA-B*57/58:01 进展者和 5 个 HLA-B*57/58:01 长期非进展者 (LTNP) 进行了纵向跟踪，我们研究了哪些补偿突变参与了从 HLA-B*57/58:01 限制性 CTL 压力中逃脱的变体的病毒适应性的恢复。 Sequence Harmony 算法用于通过比较从 HLA-B*57/58:01 阳性和阴性的 HIV-1 患者以及从 HLA-B*57/58:01 进展者和 LTNP 获得的纵向 Gag 序列来检测氨基酸组成的同源性。尽管从 HLA-B*57/58:01 个体分离的病毒含有多个 CTL 逃逸突变，但这些逃逸突变与疾病进展无关。在 HLA-B*57/58:01 进展子的序列中，观察到 Gag 中另外 5 个突变：S126N、L215T、H219Q、M228I 和 N252H。这些突变的组合恢复了 CTL 逃逸 HIV-1 变体的复制适应性。此外，我们观察到Gag中逃逸突变和补偿突变的数量与从HLA-B*57/58:01患者中分离出的生物HIV-1变异体的复制适应性之间存在正相关性，这表明HLA-B*57/58:01逃逸变异体的复制适应性是通过补偿突变的积累而恢复的。
Expression of HLA-B*57 and the closely related HLA-B*58:01 are associated with prolonged survival after HIV-1 infection. However, large differences in disease course are observed among HLA-B*57/58:01 patients. Escape mutations in CTL epitopes restricted by these HLA alleles come at a fitness cost and particularly the T242N mutation in the TW10 CTL epitope in Gag has been demonstrated to decrease the viral replication capacity. Additional mutations within or flanking this CTL epitope can partially restore replication fitness of CTL escape variants. Five HLA-B*57/58:01 progressors and 5 HLA-B*57/58:01 long-term nonprogressors (LTNPs) were followed longitudinally and we studied which compensatory mutations were involved in the restoration of the viral fitness of variants that escaped from HLA-B*57/58:01-restricted CTL pressure. The Sequence Harmony algorithm was used to detect homology in amino acid composition by comparing longitudinal Gag sequences obtained from HIV-1 patients positive and negative for HLA-B*57/58:01 and from HLA-B*57/58:01 progressors and LTNPs. Although virus isolates from HLA-B*57/58:01 individuals contained multiple CTL escape mutations, these escape mutations were not associated with disease progression. In sequences from HLA-B*57/58:01 progressors, 5 additional mutations in Gag were observed: S126N, L215T, H219Q, M228I and N252H. The combination of these mutations restored the replication fitness of CTL escape HIV-1 variants. Furthermore, we observed a positive correlation between the number of escape and compensatory mutations in Gag and the replication fitness of biological HIV-1 variants isolated from HLA-B*57/58:01 patients, suggesting that the replication fitness of HLA-B*57/58:01 escape variants is restored by accumulation of compensatory mutations.
登录
查看更多内容
影响因子：
6.7
作者：
Chopera DR;Woodman Z;Mlisana K;Mlotshwa M;Martin DP;Seoighe C;Treurnicht F;de Rosa DA;Hide W;Karim SA;Gray CM;Williamson C;CAPRISA 002 Study Team
通讯作者：
CAPRISA 002 Study Team
影响因子：
5.4
作者：
Brockman, Mark A.;Schneidewind, Arne;Allen, Todd M.
通讯作者：
Allen, Todd M.
影响因子：
6.4
作者：
Kent, SJ;Woodward, A;Zhao, A
通讯作者：
Zhao, A
影响因子：
5.4
作者：
Brockman, Mark A.;Brumme, Zabrina L.;Allen, Todd M.
通讯作者：
Allen, Todd M.
DOI：
10.1084/jem.20072457
发表时间：
2008-05-12
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Goepfert PA;Lumm W;Farmer P;Matthews P;Prendergast A;Carlson JM;Derdeyn CA;Tang J;Kaslow RA;Bansal A;Yusim K;Heckerman D;Mulenga J;Allen S;Goulder PJ;Hunter E
通讯作者：
Hunter E