Independent effects of genetic variations in mannose-binding lectin influence the course of HIV disease: The advantage of heterozygosity for coding mutations
Independent effects of genetic variations in mannose-binding lectin influence the course of HIV disease: The advantage of heterozygosity for coding mutations
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DOI：
10.1086/588712
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发表时间：
2008-07-01
影响因子：
6.4
通讯作者：
Ahuja, Sunil K.
中科院分区：
文献类型：
--
作者：
Catano, Gabriel;Agan, Brian K.;Ahuja, Sunil K.
背景甘露糖结合凝集素（MBL）是一种参与先天免疫的分子，其在体内对人类免疫缺陷病毒（HIV）-1感染和艾滋病发病机制的影响尚不清楚。共筛选了1102例HIV阳性和2213例HIV阴性成人受试者的MBL 2（编码MBL的基因）编码区和启动子区多态性。MBL 2的变异不影响获得HIV-1的风险。MBL 2编码突变的杂合性（O等位基因）和-221启动子多态性的纯合性（X等位基因）分别与疾病进展的延迟和加速相关。MBL 2变异影响进展为艾滋病定义疾病的速度。在多变量模型中，MBL 2变异的影响与已知影响疾病进展的几个参数无关，包括稳态病毒载量、基线CD 4（+）T细胞计数和迟发型超敏反应皮肤试验反应（细胞介导免疫的体内标志物）。MBL 2变异的影响在那些具有CCR 5保护基因型和高拷贝数CCL 3L 1（最有效的HIV抑制CCR 5配体）的患者中最为明显。MBL 2基因型是HIV疾病进展的独立决定因素，MBL 2编码突变的杂合性赋予疾病延迟效应。MBL依赖性免疫应答可能在HIV感染的发病机制中起作用。
Background. The in vivo impact of mannose-binding lectin (MBL), a molecule involved in innate immunity, on the pathogenesis of human immunodeficiency virus (HIV)-1 infection and AIDS is unknown.Methods. A total of 1102 HIV-positive and 2213 HIV-negative adult subjects were screened for polymorphisms in the coding and promoter regions of MBL2, the gene that encodes MBL.Results. Variations in MBL2 did not influence the risk of acquiring HIV-1. Heterozygosity for coding mutations (O allele) and homozygosity for the-221 promoter polymorphism (X allele) in MBL2 were associated with a delay in and an accelerated rate of disease progression, respectively. MBL2 variations influenced the rate of progression to AIDS-defining illnesses. In a multivariate model, the effects of MBL2 variations were independent of several parameters known to influence disease progression, including steady-state viral load, baseline CD4(+) T cell counts, and delayed-type hypersensitivity skin test responses, an in vivo marker of cell-mediated immunity. The effects of MBL2 variations were most evident in those who possessed protective genotypes of CCR5 and a high copy number of CCL3L1, the most potent HIV-suppressive CCR5 ligand.Conclusions. MBL2 genotypes are independent determinants of HIV disease progression and heterozygosity for MBL2 coding mutations confer disease-retarding effects. MBL-dependent immune responses may play a role in the pathogenesis of HIV infection.