HIV-1Vpu适应性突变体拮抗北平顶猴Tetherin的分子机制及作用研究

缺乏感染HIV-1动物模型是限制艾滋病研究的关键瓶颈。平顶猴是唯一易感HIV-1的旧大陆猴。我们首次阐明平顶猴TRIMCyp限制功能丧失是其易感HIV-1机制，创建了HIV-1感染北平顶猴模型，HIV-1在体内呈长期低水平复制。我们前期从stHIV-1sv感染猴体内分离到一株具高复制能力病毒，其Vpu突变为Vpu（G53D）。我们提出假说：HIV-1为拮抗北平顶猴Tetherin的限制，在体内高效复制，Vpu产生适应性突变。项目拟在前期基础上：鉴定各种Vpu适应性突变体；明确Vpu突变体降解北平顶猴Tetherin机制；构建含Vpu突变体的新型重组stHIV-1sv毒株并研究其抵抗IFN和抑制NF-κB信号通路作用；建立重组stHIV-1sv感染北平顶猴模型及研究病毒-免疫特征。研究将有助于构建HIV-1复制水平高、具有临床症状的HIV-1感染北平顶猴模型。

The lack of suitable HIV-1 animal models has become a key bottleneck to limit the research of AIDS. Pig-tailed macaques are the only old world monkeys susceptible to HIV-1. We elucidated that the loss of the restricted function of TRIMCyp was the mechanism of their susceptibility to HIV-1. We established a model of Northern pig-tailed macaques(NPMs) infected with HIV-1, and found the replication of HIV-1 in vivo was low for a long time. We isolated a highly replicable virus from stHIV-1sv infected NPMs, and its Vpu mutated to Vpu(G53D). We hypothesized that HIV-1 could antagonize the restriction of Tetherin of NPMs and replicate efficiently in vivo, and the Vpu produced adaptive mutation. On the basis of this work, this project aims to identify various Vpu adaptive mutants, clarify the mechanism of degradation of Tetherin of NPMs by Vpu mutants, construct a new recombinant stHIV-1sv strain containing Vpu mutants and study its resistance to IFN and inhibition of NF-κB signaling pathway, and establish a NPMs model for AIDS research using recombinant stHIV-1sv and study the characteristics of virus-immune. The study will be helpful to construct the HIV-1 infected NPMs model with high level replication of HIV-1 and clinical symptom.