Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection.
Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection.
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DOI：
10.1371/journal.ppat.1004954
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发表时间：
2015-06
期刊：
影响因子：
6.7
通讯作者：
Goulder PJ
中科院分区：
文献类型：
--
作者：
Adland E;Paioni P;Thobakgale C;Laker L;Mori L;Muenchhoff M;Csala A;Clapson M;Flynn J;Novelli V;Hurst J;Naidoo V;Shapiro R;Huang KH;Frater J;Prendergast A;Prado JG;Ndung'u T;Walker BD;Carrington M;Jooste P;Goulder PJ
HLA I类基因多态性对成人HIV疾病进展有重要影响。介导这种效应的一个重要机制是响应HLA限制性CD 8 + T细胞应答而选择的逃逸突变对病毒复制能力（VRC）的影响。导致儿科HIV感染进展缓慢的因素还不太清楚。我们在此研究VRC与小儿感染疾病进展的关系，以及HLA对VRC和成人及小儿感染疾病结局的影响。通过研究南非一个超过350名ART初治的HIV感染儿童及其母亲的队列，我们首次观察到儿科疾病进展与VRC显著相关。正如预期的那样，母子对中的VRC是强相关的（p = 0.004）。保护性HLA等位基因HLA-B*57、HLA-B*58：01和HLA-B*81：01的影响导致成人的VRC显著降低（p<0.0001），但在儿童中则不然。类似地，在成人中，而不是在儿童中，VRC在表达疾病易感等位基因HLA-B*18：01/45：01/58：02的受试者中显著更高（p = 0.007）。不考虑受试者，VRC与每种病毒中存在的由HLA-B*57/58：01/81：01驱动的Gag CD 8 + T细胞逃逸突变体的数量强烈相关（p = 0.0002）。与VRC对成人和儿童疾病进展的影响不同，HLA对疾病结局的影响在成人中很大，在感染儿童中很小，统计学上不显著。这些数据进一步强调了VRC在成人和儿童疾病进展中的重要作用，并证明了HLA非依赖性因素（尚未完全定义）是儿童非进展的主要原因。HLA在决定成人HIV感染的疾病结局中起着核心作用。介导这种HLA效应的主要机制是通过病毒复制能力（VRC），保护性HLA等位基因如HLA-B*57驱动减少VRC的病毒逃逸突变体的选择。然而，导致感染儿童中观察到的不同疾病进展率的因素仍然不确定。我们在此探讨南非金伯利的一个大型队列中HLA和VRC在儿科疾病进展中的作用。研究结果强调了VRC在成人和儿童疾病进展中的一致和重要作用。然而，关键HLA分子在成人感染中形成疾病结果的影响在儿科感染中明显缺失。因此，对儿科感染的进一步研究提供了对HIV疾病非进展的HLA非依赖性机制的重要新见解，这些机制在HIV感染但健康的ART初治儿童中占主导地位。了解这些机制仍然直接关系到未来的干预措施，以尽量减少艾滋病毒疾病的发展。
HLA class I polymorphism has a major influence on adult HIV disease progression. An important mechanism mediating this effect is the impact on viral replicative capacity (VRC) of the escape mutations selected in response to HLA-restricted CD8+ T-cell responses. Factors that contribute to slow progression in pediatric HIV infection are less well understood. We here investigate the relationship between VRC and disease progression in pediatric infection, and the effect of HLA on VRC and on disease outcome in adult and pediatric infection. Studying a South African cohort of >350 ART-naïve, HIV-infected children and their mothers, we first observed that pediatric disease progression is significantly correlated with VRC. As expected, VRCs in mother-child pairs were strongly correlated (p = 0.004). The impact of the protective HLA alleles, HLA-B*57, HLA-B*58:01 and HLA-B*81:01, resulted in significantly lower VRCs in adults (p<0.0001), but not in children. Similarly, in adults, but not in children, VRCs were significantly higher in subjects expressing the disease-susceptible alleles HLA-B*18:01/45:01/58:02 (p = 0.007). Irrespective of the subject, VRCs were strongly correlated with the number of Gag CD8+ T-cell escape mutants driven by HLA-B*57/58:01/81:01 present in each virus (p = 0.0002). In contrast to the impact of VRC common to progression in adults and children, the HLA effects on disease outcome, that are substantial in adults, are small and statistically insignificant in infected children. These data further highlight the important role that VRC plays both in adult and pediatric progression, and demonstrate that HLA-independent factors, yet to be fully defined, are predominantly responsible for pediatric non-progression. HLA plays a central role in determining disease outcome in adult HIV infection. A principal mechanism by which this HLA effect is mediated is via viral replicative capacity (VRC), protective HLA alleles such as HLA-B*57 driving the selection of viral escape mutants that reduce VRC. The factors contributing to the diverse disease progression rates observed in infected children, however, remain uncertain. We here address the role of HLA and VRC in pediatric disease progression in a large cohort in Kimberley, South Africa. The findings highlight the consistent and important role of VRC in both adult and pediatric progression. However, the impact of key HLA molecules in shaping disease outcome in adult infection is notably absent in pediatric infection. Further studies of pediatric infection therefore provide the potential to gain critical new insights into HLA-independent mechanisms of HIV disease non-progression that predominate in HIV-infected but healthy, ART-naive children. Understanding these mechanisms remains of direct relevance to the development of future interventions to minimize HIV disease.
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DOI：
10.1126/science.1254031
发表时间：
2014-07-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Carlson JM;Schaefer M;Monaco DC;Batorsky R;Claiborne DT;Prince J;Deymier MJ;Ende ZS;Klatt NR;DeZiel CE;Lin TH;Peng J;Seese AM;Shapiro R;Frater J;Ndung'u T;Tang J;Goepfert P;Gilmour J;Price MA;Kilembe W;Heckerman D;Goulder PJ;Allen TM;Allen S;Hunter E
通讯作者：
Hunter E
影响因子：
64.8
作者：
Goulder, PJR;Brander, C;Walker, BD
通讯作者：
Walker, BD
影响因子：
4.4
作者：
Honeyborne, Isobella;Rathod, Almas;Goulder, Philip J. R.
通讯作者：
Goulder, Philip J. R.
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