Structurally dissecting APOBEC3's for HIV-1 restriction

 描述(申请人提供)：随着全球艾滋病流行开始其第四个十年，全球约有3400万艾滋病毒携带者-艾滋病患者，艾滋病毒-1的治愈或疫苗仍是我们无法找到的。幸运的是，针对艾滋病毒生命周期不同阶段的七类30多种药物改善了艾滋病毒感染者的整体质量和预期寿命。到目前为止，最成功的抗病毒药物取消了艾滋病毒酶的功能。然而，来自不同分支的病毒多样性或粘附性差导致出现抗药性，阻碍了许多艾滋病毒感染的治疗控制，因此需要确定新的目标和治疗策略。我们的长期目标是 通过激活人类限制因子的天然抗艾滋病毒功能，开发新的、互补的抗病毒策略。APOBEC3(A3)家族的单域和双域胞苷脱氨酶，特别是A3G，是这种限制的关键酶，其分子机制可能被用来开发这种宿主激活的治疗策略。我们假设，A3s对核酸和HIV-1 Vif的分子相互作用和不同的特异性提供了表位，一旦表征，这些表位将为未来的治疗开发提供靶点。

 DESCRIPTION (provided by applicant): As the worldwide AIDS epidemic begins its fourth decade, with ~34 million people living with HIV-AIDS around the globe, a cure or vaccine for HIV-1 still eludes us. Fortunately over 30 drugs that belong to seven classes targeting various stages in the life cycle of HIV have improved the overall quality and life expectancy of HIV-infected patients. To date, the most successful anti-viral HIV drugs abrogate functions of HIV enzymes. However, viral diversity from varied clades or poor adherence has led to the emergence of drug resistance preventing the therapeutic control of many HIV infections, warranting the identification of novel targets and therapeutic strategies. Our long-term goal is to develop new, complementary, anti-viral strategies by activating the natural anti-HIV functions of human restriction factors. The APOBEC3 (A3) family of single and double domain cytidine deaminases, particularly A3G, are critical enzymes in this restriction and whose molecular mechanisms may be leveraged in developing such host activated therapeutic strategies. We hypothesize that the molecular interactions and differential specificities of A3s to nucleic acids and HIV-1 Vif provide epitopes that once characterized will provide target sites for future therapeutic development.