HIV Host-Cell Interactions

项目总结/摘要 人体免疫缺陷病毒（HIV）是由宿主细胞因子对抗的，称为“限制因子” 具有显著控制病毒复制并影响疾病进展和病毒感染的潜力。 传输我们的假设是，限制因子的活性和细胞的生长之间的临界平衡， 病毒对抗或逃避这些因子的能力在HIV进化中起着重要作用， 最终，我们治愈这种感染的能力。虽然一些限制因素对艾滋病毒非常有效，但其他 在人类中效果不佳，或者在人类群体中具有多态性，具有活性和非活性版本。 在限制因子的APOBEC 3基因座中，APOBEC 3 H突出，因为一些人使APOBEC 3 H活化。 这种蛋白质的不同版本，而其他版本则没有，而新发现的APOBEC 3C多态性 在人类的一个子集中增加活动。所有APOBEC 3蛋白的拮抗作用都依赖于 HIV-1 Vif蛋白本身是多态性的，必须同时攻击多种宿主蛋白。 我们将继续研究限制性因素对艾滋病毒的相互作用， 病毒来自具有不同APOBEC 3蛋白库的个体的后果。我们将使用 一个已经建立的不一致夫妇队列，以了解Vif蛋白的进化和功能， 当病毒从具有一种APOBEC 3 H基因型的个体传播给具有不同基因型的个体时， APOBEC 3 H基因型。与此同时，我们还将利用非洲绿色猴的自然感染 （AGM）具有不同SIV的亚种，以了解APOBEC 3基因座的多态性如何影响 慢病毒与宿主关系的演变此外，我们将确定重要性和 APOBEC 3C中功能获得性多态性的机制。我们将进一步研究进化 Vif-APOBEC 3相互作用的潜力，通过确定SIV Vif蛋白适应 拮抗人APOBEC 3库。最后，我们启动了一项创新和灵活的 CRISPR/Cas9筛选新的限制性因子，这将进一步了解相互作用 影响病毒复制的基因。总的来说，本提案的目标是了解如何 这些限制因子的进化和功能影响HIV在人体内的复制。

Project Summary/Abstract The human immunodeficiency virus (HIV) is opposed by host cell factors, called “restriction factors” with the potential to significantly control viral replication and affect disease progression and viral transmission. Our hypothesis is that the critical balance between the activity of restriction factors and the ability of the virus to antagonize or evade these factors plays in important role in HIV evolution, and ultimately, our ability to cure this infection. While some restriction factors are very active against HIV, others work poorly in humans or are polymorphic in the human population with both active and inactive versions. In the APOBEC3 locus of restriction factors, APOBEC3H stands out because some humans make active versions of this protein, while others do not, and a newly discovered polymorphism in APOBEC3C has increased activity in a subset of humans. Antagonism of all of the APOBEC3 proteins is dependent on the activity of the HIV-1 Vif protein which itself is polymorphic and must attack multiple host proteins at once. We will continue our studies on the interactions of restriction factors against HIV by determining the consequences of virus going from individuals with differing repertoires of APOBEC3 proteins. We will use an already established discordant couples cohort to understand the evolution and function of Vif proteins when virus is transmitted from an individual with one APOBEC3H genotype to a person with a different APOBEC3H genotype. In parallel, we will also exploit the natural infection of African Green Monkeys (AGMs) subspecies with divergent SIVs to understand how polymorphism in the APOBEC3 locus affects the evolution of the lentivirus-host relationship. In addition, we will determine the importance and mechanism of a gain-of-function polymorphism in APOBEC3C. We will further study the evolutional potential of Vif-APOBEC3 interactions by determining the steps needed for SIV Vif proteins to adapt to antagonize the human APOBEC3 repertoire. Finally, we have initiated an innovative and flexible CRISPR/Cas9 screen for novel restriction factors that will provide further insights into the interactions between HIV and its host that affect virus replication. Overall, the goal of this proposal is to understand how the evolution and function of these restriction factors impacts HIV replication in humans.