Effect of DC-SIGNR Polymorphisms on HIV-1 Infection

描述(由申请人提供)：以前的研究提供的证据表明，尽管多次接触艾滋病毒-I，但很少有人保持血清阴性，并且不会感染艾滋病毒-1。宿主基因的多态可能在这些暴露于血清阴性(ES)的个体对HIV-1感染的明显抵抗力和疾病进展的不同速度中发挥关键作用。然而，与HIV-1感染相关的一些基因多态性的影响可能仅限于某些人群，而在其他种族群体中没有发现。此外，这些等位基因的影响也没有得到一致的证明。在对这一建议的初步研究中，我们对ES、HIV-1感染者和HIV-1血清阴性个体进行了CCR5-A32、CCR5启动子、CCR2-641、SDF-1-3‘A、RANTES-403A和-28G等已知基因多态性的调查。根据其他研究小组的报告，CCR5-A32纯合子与HIV-1感染几率降低有关，但没有发现其他已知的多态性与对HIV-1感染的抵抗力有关。此外，还研究了树突状细胞(DC)特异性细胞间黏附分子-3抓取非整合素(DC-SIGN)及其同源物DC-SIGNR的多态性。DC-SIGNR7/7纯合子重复与HIV-1感染几率增加相关，而杂合7/5或纯合子5/5与对HIV-1感染的抵抗力相关。5重复等位基因可能是HIV-I的显性抗性因子，第7重复等位基因可能是HIV-I感染的隐性危险因素。提示DC-SIGNR基因多态性在HIV-1传播中可能起一定作用。在这项建议中，我们将在更多的人群中更严格地解决这些问题，并通过以下具体目标研究DC-SIGNR基因多态影响艾滋病毒-1传播和疾病进展的机制：1)确定DC-SIGNR多态对艾滋病毒-1传播、疾病进展的影响，以及艾滋病毒-1在地理位置(美国、秘鲁、中国和南非)大流行的影响；2)通过测定DC-SIGNR等位基因的表达和功能来确定DC-SIGNR基因多态影响艾滋病毒-1传播和疾病进展的机制。这些研究应有助于确定新的治疗目标和战略，以防止艾滋病毒-1传播和控制疾病进展。

DESCRIPTION (provided by applicant): Previous studies provide evidence that rare individuals remain seronegative and do not acquire HIV-1 infection despite multiple high-risk exposures to HIV-I. Polymorphisms in host genes may play critical roles in the apparent resistance to HIV-1 infection of these exposed seronegative (ES) individuals and in the variable rates of disease progression. However, the influence of some genetic polymorphisms associated with HIV-1 infection may be restricted to certain populations and not found in other ethnic groups. Furthermore, the effect of these alleles has been demonstrated inconsistently. In our preliminary studies of this proposal, the cohorts of ES, HIV-1 infected and HIV-1 seronegative individuals were investigated for such known polymorphisms including CCR5-A32, CCR5 promoter, CCR2-641, SDF-1-3'A, RANTES -403A and -28G. As reported by other groups, homozygous CCR5-A32 was associated with decreased chance of HIV-1 infection but no other known polymorphisms were found to be associated with the resistance to HIV-1 infection. In addition, polymorphisms of dendritic cell (DC)-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and its related homologue, DC-SIGNR were investigated. The homozygous DC-SIGNR 7/7 repeat was associated with an increased probability of HIV-1 infection, whereas the heterozygous 7/5 or homozygous 5/5 correlated with resistance to HIV-1 infection. The 5 repeat allele may act as a dominant resistance factor, while the 7 repeat allele may serve as a recessive risk factor for acquiring HIV-I. These findings suggest that the DC-SIGNR genetic polymorphisms may play a role in HIV-1 transmission. In this proposal, we will address these issues more rigorously in a larger population and investigate the mechanisms for the effect of DC-SIGNR genetic polymorphisms on HIV-1 transmission and disease progression by the following specific aims: 1) To determine the impact of DC-SIGNR polymorphisms on HIV-1 transmission, disease progression, and the HIV-1 pandemic at geographic sites (United States, Peru, China and South Africa); 2) To define the mechanisms for the effect of DC-SIGNR polymorphisms on HIV-1 transmission and disease progression by determining the expression and function of DC-SIGNR alleles. These studies should assist in the identification of new therapeutic targets and strategies to protect against HIV-1 transmission and control disease progression.