HIV-1 disease-influencing effects associated with ZNRD1, HCP5 and HLA-C alleles are attributable mainly to either HLA-A10 or HLA-B*57 alleles.
HIV-1 disease-influencing effects associated with ZNRD1, HCP5 and HLA-C alleles are attributable mainly to either HLA-A10 or HLA-B*57 alleles.
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DOI：
10.1371/journal.pone.0003636
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Ahuja, Sunil K.
中科院分区：
文献类型：
--
作者：
Catano, Gabriel;Kulkarni, Hemant;He, Weijing;Marconi, Vincent C.;Agan, Brian K.;Landrum, Michael;Anderson, Stephanie;Delmar, Judith;Telles, Vanessa;Song, Li;Castiblanco, John;Clark, Robert A.;Dolan, Matthew J.;Ahuja, Sunil K.
最近的一项全基因组关联研究表明，HCP5、HLAC和ZNRD1基因及其周围的多态对HIV-1病毒的复制或疾病进展具有限制作用。在这里，我们还发现这些等位基因与HIV疾病的不同方面有关，尽管主要是在欧洲裔美国人中。此外，我们提出，因为GWA群是HIV阳性个体的一个子集，部分是基于病毒载量低而选择的，与我们在HIV-1感染者的大量特征良好的预期自然病史队列中检测到的病毒载量的相关性相比，观察到的病毒载量的相关性被放大。我们还发现，由于连锁不平衡(LD)模式，ZNRD1或HLA-C和HCP5等位基因的显性病毒载量和影响疾病的关联主要当这些等位基因分别出现在包含HLA-A10或HLA-B*57的单倍型中时明显。缺乏HLAA10的ZNRD1等位基因不具有疾病保护作用，而ZNRD1A10单倍型具有保护作用。单独检测时，HCP5-G等位基因与缓慢的病程和较低的病毒载量有关。然而，在多变量模型中，在分离出B*57的保护作用后，HCP5-G等位基因与疾病加速和增强病毒复制有关；这些与HCP5-G的关联在其他方面被掩盖，因为该等位基因与保护B*57等位基因的子集之间具有非常强的LD。此外，HCP5和HLA-C等位基因将含有B*57的等位基因分成与显著的疾病迟缓或进展性疾病相关的那些，这为为什么一些携带HL A-B*57的个体是长期无进展性的人，而另一些人表现为进展性疾病的长期难题提供了一种解释。总而言之，这些数据总体上强调了基因型-表型关系对队列设计、表型选择、LD模式和研究人群的强烈依赖性。他们特别证明了ZNRD1等位基因对疾病进展速度的影响归因于人类白细胞抗原-A10，有助于阐明HCP5、人类白细胞抗原C和人类白细胞抗原B*57等位基因之间的关系，并重申了人类白细胞抗原B*57等位基因在HIV疾病中的关键作用。此外，由于保护性的B*57基因型别传递着显著的有益效果，与它们对病毒控制的强烈影响无关，可以想象，旨在减少病毒载量的基于T细胞的治疗性疫苗策略可能不足以限制艾滋病的进展，这增加了针对病毒载量无关致病决定因素的补充策略的潜在需要。
A recent genome-wide association study (GWAS) suggested that polymorphisms in or around the genes HCP5, HLA-C and ZNRD1 confer restriction against HIV-1 viral replication or disease progression. Here, we also find that these alleles are associated with different aspects of HIV disease, albeit mainly in European Americans. Additionally, we offer that because the GWAS cohort was a subset of HIV-positive individuals, selected based in part on having a low viral load, the observed associations for viral load are magnified compared with those we detect in a large well-characterized prospective natural history cohort of HIV-1-infected persons. We also find that because of linkage disequilibrium (LD) patterns, the dominant viral load- and disease-influencing associations for the ZNRD1 or HLA-C and HCP5 alleles are apparent mainly when these alleles are present in HLA-A10- or HLA-B*57-containing haplotypes, respectively. ZNRD1 alleles lacking HLA-A10 did not confer disease protection whereas ZNRD1-A10 haplotypes did. When examined in isolation, the HCP5-G allele associates with a slow disease course and lower viral loads. However, in multivariate models, after partitioning out the protective effects of B*57, the HCP5-G allele associates with disease-acceleration and enhanced viral replication; these associations for HCP5-G are otherwise obscured because of the very strong LD between this allele and a subset of protective B*57 alleles. Furthermore, HCP5 and HLA-C alleles stratify B*57-containing genotypes into those that associate with either striking disease retardation or progressive disease, providing one explanation for the long-standing conundrum of why some HLA-B*57-carrying individuals are long-term non-progressors, whereas others exhibit progressive disease. Collectively, these data generally underscore the strong dependence of genotype-phenotype relationships upon cohort design, phenotype selection, LD patterns and populations studied. They specifically demonstrate that the influence of ZNRD1 alleles on disease progression rates are attributable to HLA-A10, help clarify the relationship between the HCP5, HLA-C and HLA-B*57 alleles, and reaffirm a critical role of HLA-B*57 alleles in HIV disease. Furthermore, as the protective B*57-containing genotypes convey striking salutary effects independent of their strong impact on viral control, it is conceivable that T cell-based therapeutic vaccine strategies aimed at reducing viral loads may be inadequate for limiting AIDS progression, raising the potential need for complementary strategies that target viral load-independent determinants of pathogenesis.
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影响因子：
82.9
作者：
Ahuja, Sunil K.;Kulkarni, Hemant;Dolan, Matthew J.
通讯作者：
Dolan, Matthew J.
影响因子：
56.9
作者：
Gonzalez, E;Kulkarni, H;Ahuja, SK
通讯作者：
Ahuja, SK
DOI：
10.1097/01.qai.0000230526.79341.83
发表时间：
2006-10-01
影响因子：
3.6
作者：
Amirfar, Sam;Hollenberg, James P.;Karim, Salim S. Abdool
通讯作者：
Karim, Salim S. Abdool
DOI：
10.1073/pnas.0803526105
发表时间：
2008-06-24
影响因子：
11.1
作者：
Burt, Trevor D.;Agan, Brian K.;Ahuja, Sunil K.
通讯作者：
Ahuja, Sunil K.
影响因子：
6.4
作者：
Catano, Gabriel;Agan, Brian K.;Ahuja, Sunil K.
通讯作者：
Ahuja, Sunil K.