Transmission of HIV-1 CTL escape variants provides HLA-mismatched recipients with a survival advantage.
Transmission of HIV-1 CTL escape variants provides HLA-mismatched recipients with a survival advantage.
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DOI：
10.1371/journal.ppat.1000033
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发表时间：
2008-03-21
期刊：
影响因子：
6.7
通讯作者：
CAPRISA 002 Study Team
中科院分区：
文献类型：
--
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
已知影响 HIV 感染者疾病进展速度的最重要遗传因素之一是 I 类人类白细胞抗原 (HLA) 基因座的基因型，它决定了细胞毒性 T 淋巴细胞 (CTL) 靶向的 HIV 肽。例如，具有 HLA-B*57 或 B*5801 等位基因的个体以 Gag 蛋白的功能重要部分为目标。逃避这些 CTL 反应的突变体可能比野生型具有较低的适应性，并且可能与较慢的疾病进展有关。逃逸变体向没有这些 HLA 等位基因的个体的传播与快速恢复为野生型有关。然而，逃逸突变体的感染是否为新感染的宿主带来优势的问题尚未得到解决。在这里，我们研究了传播病毒的基因型与疾病进展的预后标志物之间的关系，并表明 HLA-B*57/B*5801 逃逸突变体的感染与较低的病毒载量和较高的 CD4+ 计数相关。感染艾滋病毒后，众所周知，一个人的基因构成是其发展为艾滋病的速度的主要决定因素。特别重要的是 I 类人类白细胞抗原 (HLA) 基因，它负责提醒免疫系统注意 HIV 的存在。我们的免疫系统无法击败 HIV 的原因之一是该病毒可能突变为我们的 HLA 基因不再识别的形式。然而，某些人的 HLA 基因版本（例如 HLA-B*57 和 HLA-B*5801）已知会迫使 HIV 耐受损害其繁殖能力的突变。 HIV 繁殖速度较慢被认为是 HLA-B*57 和 HLA-B*5801 阳性人群发展为艾滋病的速度比大多数其他 HIV 感染者慢的原因之一。我们在此报告一项针对 HLA-B*57 和 HLA-B*5801 阴性女性的研究，其中更好地控制疾病往往与她们感染了携带突变的病毒有关，这些突变先前已被证明会减少复制。这些突变是感染 HLA-B*57 和 HLA-B*5801 阳性人群的病毒的特征。这首次表明，感染此类生殖受损病毒的 HLA-B*57 或 HLA-B*5801 阴性人群也可能经历更好的生存前景。
One of the most important genetic factors known to affect the rate of disease progression in HIV-infected individuals is the genotype at the Class I Human Leukocyte Antigen (HLA) locus, which determines the HIV peptides targeted by cytotoxic T-lymphocytes (CTLs). Individuals with HLA-B*57 or B*5801 alleles, for example, target functionally important parts of the Gag protein. Mutants that escape these CTL responses may have lower fitness than the wild-type and can be associated with slower disease progression. Transmission of the escape variant to individuals without these HLA alleles is associated with rapid reversion to wild-type. However, the question of whether infection with an escape mutant offers an advantage to newly infected hosts has not been addressed. Here we investigate the relationship between the genotypes of transmitted viruses and prognostic markers of disease progression and show that infection with HLA-B*57/B*5801 escape mutants is associated with lower viral load and higher CD4+ counts. Following infection with HIV, it is well established that a person's genetic makeup is a major determinant of how quickly they will progress to AIDS. Particularly important is the class I Human leukocyte antigen (HLA) gene that is responsible for alerting the immune system to HIV's presence. One of the reasons our immune systems are unable to beat HIV is that the virus can mutate to forms that our HLA genes no longer recognise. However, some people have versions of the HLA gene (for example HLA-B*57 and HLA-B*5801) that are known to force HIV to tolerate mutations that damage its ability to reproduce. Slower HIV reproduction is thought to be one reason that HLA-B*57 and HLA-B*5801 positive people progress to AIDS more slowly than most other HIV infected persons. We report here on a study of HLA-B*57 and HLA-B*5801 negative women in which better control of disease tended to be associated with their being infected with viruses carrying mutations that have been previously shown to reduce replication. These mutations characterise viruses found infecting HLA-B*57 and HLA-B*5801 positive people. This indicates for the first time that HLA-B*57 or HLA-B*5801 negative people that are infected by such reproductively compromised viruses may also experience better survival prospects.
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CTL逃生变体的传播和积累驱动HIV多态性与HLA之间的负相关。
影响因子：
15.3
作者：
Leslie, A;Kavanagh, D;Honeyborne, I;Pfafferott, K;Edwards, C;Pillay, T;Hilton, L;Thobakgale, C;Ramduth, D;Draenert, R;Le Gall, S;Luzzi, G;Edwards, A;Brander, C;Sewell, AK;Moore, S;Mullins, J;Moore, C;Mallal, S;Bhardwaj, N;Yusim, K;Phillips, R;Klenerman, P;Korber, B;Kiepiela, P;Walker, B;Goulder, P
通讯作者：
Goulder, P
HIV-1 GAG中的簇突变是逃避HLA-B27限制的细胞毒性T淋巴细胞反应所必需的。
影响因子：
15.3
作者：
Kelleher, A D;Long, C;Holmes, E C;Allen, R L;Wilson, J;Conlon, C;Workman, C;Shaunak, S;Olson, K;Goulder, P;Brander, C;Ogg, G;Sullivan, J S;Dyer, W;Jones, I;McMichael, A J;Rowland-Jones, S;Phillips, R E
通讯作者：
Phillips, R E
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：
1.5
作者：
Fang, GW;Burger, H;Weiser, B
通讯作者：
Weiser, B
影响因子：
82.9
作者：
Goulder, PJR;Phillips, RE;RowlandJones, S
通讯作者：
RowlandJones, S