Temporal association of HLA-B*81:01- and HLA-B*39:10-mediated HIV-1 p24 sequence evolution with disease progression.
Temporal association of HLA-B*81:01- and HLA-B*39:10-mediated HIV-1 p24 sequence evolution with disease progression.
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HLA-B*81:01- 和 HLA-B*39:10 介导的 HIV-1 p24 序列进化与疾病进展的时间关联。
DOI：
10.1128/jvi.00539-12
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发表时间：
2012
影响因子：
5.4
通讯作者：
CAPRISA002StudyTeam
中科院分区：
文献类型：
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作者：
Ntale,RS;Chopera,DR;Ngandu,NK;AssisdeRosa,D;Zembe,L;Gamieldien,H;Mlotshwa,M;Werner,L;Woodman,Z;Mlisana,K;AbdoolKarim,S;Gray,CM;Williamson,C;CAPRISA002StudyTeam
HLA-B*81:01和HLA-B*39:10等位基因与HIV-1亚型C感染的病毒毒控制有关。这两个等位基因都限制了p24 Gag的TL9表位，并且细胞毒性t淋巴细胞（CTL）介导的该表位的逃逸突变与病毒的蛋白体外适应性成本有关。我们研究了TL9表位突变对5例B*81:01-和2例B*39:10阳性c型感染个体疾病进展的时间和影响。虽然在感染后2个月取样的B*39:10参与者都有TL9表位突变的病毒，但在5名（3/5）B*81:01参与者中，有3名在感染后10个月才检测到TL9逃逸突变，需要额外的10至15个月才能达到固定。在剩下的两个B*81:01个体中，一个在感染后2周携带TL9逃逸变异，而另一个参与者在感染后长达33个月的病毒中未检测到逃逸突变，尽管CTL靶向了表位。在所有参与者中，TL9的逃逸突变与已知与宿主趋向性相关的Gag区域的共同进化残基有关。TL9的晚期逃逸，加上假定的代偿性突变的共同进化，与两个控制感染的个体的病毒载量自发增加相吻合。这些结果提供了B*81:01介导的病毒进化在单个Gag p24表位上对病毒血症控制的有害影响的活体证据。
HLA-B*81:01 and HLA-B*39:10 alleles have been associated with viremic control in HIV-1 subtype C infection. Both alleles restrict the TL9 epitope in p24 Gag, and cytotoxic-T-lymphocyte (CTL)-mediated escape mutations in this epitope have been associated with anin vitrofitness cost to the virus. We investigated the timing and impact of mutations in the TL9 epitope on disease progression in five B*81:01- and two B*39:10-positive subtype C-infected individuals. Whereas both B*39:10 participants sampled at 2 months postinfection had viruses with mutations in the TL9 epitope, in three of the five (3/5) B*81:01 participants, TL9 escape mutations were only detected 10 months after infection, taking an additional 10 to 15 months to reach fixation. In the two remaining B*81:01 individuals, one carried a TL9 escape variant at 2 weeks postinfection, whereas no escape mutations were detected in the virus from the other participant for up to 33 months postinfection, despite CTL targeting of the epitope. In all participants, escape mutations in TL9 were linked to coevolving residues in the region of Gag known to be associated with host tropism. Late escape in TL9, together with coevolution of putative compensatory mutations, coincided with a spontaneous increase in viral loads in two individuals who were otherwise controlling the infection. These results providein vivoevidence of the detrimental impact of B*81:01-mediated viral evolution, in a single Gag p24 epitope, on the control of viremia.