pol Gene Products, Human Immunodeficiency Virus

  • 文章类型: Journal Article
    获得性免疫缺陷综合症(AIDS)是由人类免疫缺陷病毒(HIV)引起的。HIV蛋白酶,逆转录酶,整合酶是目前治疗这种疾病的药物的靶点。然而,由于病毒的高突变率,抗病毒耐药株迅速出现,导致对新药开发的需求。一个有吸引力的靶标是Gag-Pol多蛋白,在艾滋病毒的生命周期中起着关键作用。最近,我们发现HIV-1整合酶中M50I和V151I突变的组合可以抑制病毒释放,抑制Gag-Pol自加工和成熟的启动,而不干扰Gag-Pol的二聚化.逆转录酶中整合酶或RNaseH结构域的其他突变可以弥补该缺陷。然而,分子机制未知。没有可用于进一步研究的全长HIV-1Pol蛋白的三级结构。因此,我们开发了一个工作流程来预测HIV-1NL4.3Pol多蛋白的三级结构.与最近公布的部分HIV-1Pol结构(PDBID:7SJX)相比,模型结构具有相当的质量。我们的HIV-1NL4.3Pol二聚体模型是第一个全长Pol三级结构。它可以为研究HIV-1Pol的自动处理机制和开发新的有效药物提供结构平台。此外,该工作流程可用于预测无法通过常规实验方法解析的其他大型蛋白质结构。
    Acquired immunodeficiency syndrome (AIDS) is caused by human immunodeficiency virus (HIV). HIV protease, reverse transcriptase, and integrase are targets of current drugs to treat the disease. However, anti-viral drug-resistant strains have emerged quickly due to the high mutation rate of the virus, leading to the demand for the development of new drugs. One attractive target is Gag-Pol polyprotein, which plays a key role in the life cycle of HIV. Recently, we found that a combination of M50I and V151I mutations in HIV-1 integrase can suppress virus release and inhibit the initiation of Gag-Pol autoprocessing and maturation without interfering with the dimerization of Gag-Pol. Additional mutations in integrase or RNase H domain in reverse transcriptase can compensate for the defect. However, the molecular mechanism is unknown. There is no tertiary structure of the full-length HIV-1 Pol protein available for further study. Therefore, we developed a workflow to predict the tertiary structure of HIV-1 NL4.3 Pol polyprotein. The modeled structure has comparable quality compared with the recently published partial HIV-1 Pol structure (PDB ID: 7SJX). Our HIV-1 NL4.3 Pol dimer model is the first full-length Pol tertiary structure. It can provide a structural platform for studying the autoprocessing mechanism of HIV-1 Pol and for developing new potent drugs. Moreover, the workflow can be used to predict other large protein structures that cannot be resolved via conventional experimental methods.
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  • 文章类型: Case Reports
    A recently diagnosed 22-year-old female with no history of transmission risk factors prompted a thorough investigation of possible alternative risk factors. As the patient had evidence of advanced disease and laboratory data compatible with long-standing infection, past events were reviewed. About 10 years ago the patient shared manicure utensils with an older cousin, later known to be HIV infected; this prompted the phylogenetic analysis of the HIV sequences of both patients. Phylogenetic analyses of partial HIV-1 polymerase and envelope sequences from both patients revealed highly related sequences, with an estimated common ancestor date (about 11 years ago) that coincided with the putative sharing of manicure instruments, during a time in which the cousin was not virally suppressed. Taken together, the information about the infection of this patient suggests the use of shared manicure instruments as an alternative route of fomite HIV-1 transmission.
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  • 文章类型: Case Reports
    In recent years, the increase of migration from countries where human immunodeficiency virus type 2 (HIV-2) is endemic to industrialized countries has facilitated the spread of the virus in individuals previously unexposed to this threat. In this report, we performed a phylogenetic analysis on pol and env sequences of HIV-2 strains identified in foreigners and native citizens to trace the origin of infection. All but one of the 17 pol gene sequences were classified as group A. HIV-2 strains were aggregated in several clusters depending by the country of origin and/or infection. One patient (1AA) was classified as being infected with a recombinant between HIV-2 group A and HIV-2 group B, because the pol gene sequence was clearly in the group A, but an env V3 region sequence from this patient was more similar to group B viruses. Therefore, it is urgent to strengthen the surveillance and use adequate molecular virological tools to diagnose and monitor HIV-2 infection.
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    文章类型: English Abstract
    HIV-1 variants circulating in the town of Cherepovets, Vologda Region, were genetically analyzed. It was shown that that were predominantly two HIV-1 variants: IDU-A (19%) and the recombinant strain UDU-AIB (77%) that circulated in the region. Amongst the IDU-A strains, there were genotypes containing characteristic secondary drug resistance mutations in the pol gene of V771 and A62V, as well as variants of the wild type. Amongst IDU-AIB strains, only one variant of the virus had genotype V771. The recombinant form of HIV-1 was more common in injective drug users while a group of heterosexuals had both recombinant virus and the variant IDU-A, that is typical of other regions of Russia. Thus, the epidemic outbreak due to the recombinant HIV-1 strain IDU-AIB was first registered in Russia, outside the Kaliningrad Region.
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