HIV is a retrovirus that infects CD4⁺ T lymphocytes in human beings and causes immunodeficiency. In the recent years, various therapies have been developed against HIV, including targeting the HIV specific protein, integrase, responsible for integration of HIV cDNA into host DNA. Although, integrase is specific to HIV, it has functional and structural similarity with RAG1, one of the partner proteins associated with V(D)J recombination, a process by which immune diversity is generated in humans. Currently, there are three HIV integrase inhibitors: Elvitegravir, Dolutegravir, and Raltegravir, in the market which have been approved by the FDA (USA). All three drugs are used in anti-retroviral therapy (ART). Previously, we showed that amongst the HIV inhibitors, Elvitegravir could significantly decrease B cell maturation in vivo and inhibit the physiological activities of RAGs in vitro, unlike Raltegravir. In the present study, we address the effect of second-generation integrase inhibitor, Dolutegravir on RAG activities. Binding and nicking studies showed that, Dolutegravir could decrease the binding efficiency of RAG1 domains and cleavage on DNA substrates, but not as considerably as Elvitegravir. Thus, we show that although the integrase inhibitors such as Elvitegravir show an affinity towards RAG1, the newer molecules may have lesser side-effects.

HIV是一种逆转录病毒，可感染人类CD4 ^{+ T淋巴细胞并导致免疫缺陷。}近年来，针对 HIV 开发了多种疗法，包括针对 HIV 特异性蛋白整合酶，该蛋白负责将 HIV cDNA 整合到宿主 DNA 中。虽然整合酶是 HIV 特有的，但它与 RAG1 具有功能和结构相似性，RAG1 是与 V(D)J 重组相关的伴侣蛋白之一，而 V(D)J 重组是人类产生免疫多样性的过程。目前，市场上有三种HIV整合酶抑制剂：Elvitegravir、Dolutegravir和Raltegravir，并已获得美国FDA批准。所有三种药物均用于抗逆转录病毒治疗（ART）。此前，我们表明，在HIV抑制剂中，与Raltegravir不同，Elvitegravir可以显着降低体内B细胞成熟并在体外抑制RAGs的生理活性。在本研究中，我们探讨了第二代整合酶抑制剂 Dolutegravir 对 RAG 活性的影响。结合和切口研究表明，Dolutegravir 可以降低 RAG1 结构域的结合效率和 DNA 底物的切割，但不如 Elvitegravir 那么显着。因此，我们表明，尽管 Elvitegravir 等整合酶抑制剂对 RAG1 表现出亲和力，但较新的分子可能具有较小的副作用。