Virion infectivity factor（Vif） is one of the six accessory proteins of HIV-1 and is necessary for viral infectivity. Human Apolipoprotein B editing complex protein 3G（h-APOBEC3G） is a cytidine deaminase only expre...Virion infectivity factor（Vif） is one of the six accessory proteins of HIV-1 and is necessary for viral infectivity. Human Apolipoprotein B editing complex protein 3G（h-APOBEC3G） is a cytidine deaminase only expressed in ＂nonpermissive＂ cells and exhibits virus suppressive activity. With the aid of a Cullin-5 E3 ligase, Vif induces h-APOBEC3G degradation and with the destruction of this ligase, Vif is functionally inactive. Therefore, it is expected that blocking this E3 pathway would be a new therapeutic strategy against HIV-1 infection. In this article, the authors＇ took sequence alignment of the N-termini of Cullin-5 and three other members of the Cullin protein family, respectively. A set of small peptides has been synthesized based on the sequence comparison results and possible Vif-Cullin-5 interaction domains. Moreover, it has been demonstrated that several peptides can reduce virus infectivity in ＂nonpermissive＂ cells with a dose-responsive manner, but not in ＂permissive＂ cells. The results also indicate that the loss of viral infectivity may be because of the increase of APOBEC3G amount in the peptide-treated cells. It is concluded that peptides derived from Cullin-5 can block the APOBEC3G degradation induced by Vif and suppress HIV-1 infectivity. Therefore this study starts a novel strategy for the development of a new HIV-1 inhibitor.展开更多
The viral infectivity factor (Vif) was found to be essential for controlling HIV-1 virus infectivity. It targets cellular antiviral proteins in APOBEC family (APO) to trigger its fast degradation and inhibits APO pack...The viral infectivity factor (Vif) was found to be essential for controlling HIV-1 virus infectivity. It targets cellular antiviral proteins in APOBEC family (APO) to trigger its fast degradation and inhibits APO packaging into nascent virion. In the present study, we propose a mathematical model to quantitatively study the intracellular dynamics of these typical virus-host interactions. Four sets of published experimental data were compared with simulation results to justify the model. Systematic parameter sensitivity and perturbation analysis showed that parameters related to APO are crucial to the infectivity of newly synthesized HIV-1 virus. Interestingly, we discovered that the synthesis rate of the viral structure protein Gag and the required number per nascent virion are optimized to achieve high virion production with minimal level of packaged APO, and large portion of model parameters are beneficial to virus only within a relatively small range. Furthermore, minor variations in several parameters related to viral protein Tat, the activator of viral RNA synthesis, were found to induce switch-like behaviors on both incorporated Vif and APO. These findings may provide new insights for understanding the high mutation rate of HIV-1 virus and its latency, as well as help identify key targets for therapeutic design.展开更多
This paper is to further understand how APOBEC3G can defend the retroviruses and to find new approaches to AIDs （acquired immure deficiency syndrome）.The viral infectivity factor （Vif） induces rapid degradation of...This paper is to further understand how APOBEC3G can defend the retroviruses and to find new approaches to AIDs （acquired immure deficiency syndrome）.The viral infectivity factor （Vif） induces rapid degradation of APOBEC3G by ubiquitination, which is a proteosome-dependent pathway. Precisely speaking, only in the virus-producing cell Vif expression is necessary; in its absence, infection of a subsequent target cell terminates at a postentry step through the action of the human APOBEC3G antiviral mechanism. Hf protein has two domains： one binds to APOBEC3G and the other regulates the degradation of APOBEC3G by a conserved sequence, SLQ （Y/F） LA motif. Recently, the research on Vif has also revealed APOBEC3G is a novel component of innate immune system. In fact, APOBEC3G not only acts in DNA editing to block the replication of retroviruses such as HIV-1, but also is able to defend a wide spectrum of distantly related retroviruses and interferes with HBV through a different mechanism from HIE.展开更多
基金the National Natural Science Foundation of China(No.30570363)Distinguished Young Scholars Fund of Jilin Province, China(No.20050112)the New Century Excellent Talents
文摘Virion infectivity factor（Vif） is one of the six accessory proteins of HIV-1 and is necessary for viral infectivity. Human Apolipoprotein B editing complex protein 3G（h-APOBEC3G） is a cytidine deaminase only expressed in ＂nonpermissive＂ cells and exhibits virus suppressive activity. With the aid of a Cullin-5 E3 ligase, Vif induces h-APOBEC3G degradation and with the destruction of this ligase, Vif is functionally inactive. Therefore, it is expected that blocking this E3 pathway would be a new therapeutic strategy against HIV-1 infection. In this article, the authors＇ took sequence alignment of the N-termini of Cullin-5 and three other members of the Cullin protein family, respectively. A set of small peptides has been synthesized based on the sequence comparison results and possible Vif-Cullin-5 interaction domains. Moreover, it has been demonstrated that several peptides can reduce virus infectivity in ＂nonpermissive＂ cells with a dose-responsive manner, but not in ＂permissive＂ cells. The results also indicate that the loss of viral infectivity may be because of the increase of APOBEC3G amount in the peptide-treated cells. It is concluded that peptides derived from Cullin-5 can block the APOBEC3G degradation induced by Vif and suppress HIV-1 infectivity. Therefore this study starts a novel strategy for the development of a new HIV-1 inhibitor.
文摘HIV-1(human immunodeficiency virus type 1)病毒感染因子Vif(viral infectivity factor)是高度保守的碱性磷酸化蛋白质,是HIV-1的辅助调节蛋白之一。Vif蛋白的主要功能是能够介导宿主细胞体内载脂蛋白BmRNA编辑酶催化多肽样蛋白3G(apolipoprotein B mRNA editing enzyme catalytic polypeptide like 3G,APOBEC3G)的降解,从而增强病毒的感染性。此外,它还具有调节病毒的逆转录和复制晚期以及诱导细胞G2期停滞等功能。目前,许多实验室已经针对Vif蛋白进行抑制剂的设计。本文简要叙述了Vif蛋白的结构与功能,并主要对其抑制剂的最新进展进行了综述。
基金supported by the National Natural Science Foundation of China (10721403)National Basic Research Program of China (2009C-B918500)the National High-Technology Research & Development Program of China (2006AA020400)
文摘The viral infectivity factor (Vif) was found to be essential for controlling HIV-1 virus infectivity. It targets cellular antiviral proteins in APOBEC family (APO) to trigger its fast degradation and inhibits APO packaging into nascent virion. In the present study, we propose a mathematical model to quantitatively study the intracellular dynamics of these typical virus-host interactions. Four sets of published experimental data were compared with simulation results to justify the model. Systematic parameter sensitivity and perturbation analysis showed that parameters related to APO are crucial to the infectivity of newly synthesized HIV-1 virus. Interestingly, we discovered that the synthesis rate of the viral structure protein Gag and the required number per nascent virion are optimized to achieve high virion production with minimal level of packaged APO, and large portion of model parameters are beneficial to virus only within a relatively small range. Furthermore, minor variations in several parameters related to viral protein Tat, the activator of viral RNA synthesis, were found to induce switch-like behaviors on both incorporated Vif and APO. These findings may provide new insights for understanding the high mutation rate of HIV-1 virus and its latency, as well as help identify key targets for therapeutic design.
基金the Cultivating Funds of Academic and Technical Leaders in Sichuan Province (No. 2200338)
文摘This paper is to further understand how APOBEC3G can defend the retroviruses and to find new approaches to AIDs （acquired immure deficiency syndrome）.The viral infectivity factor （Vif） induces rapid degradation of APOBEC3G by ubiquitination, which is a proteosome-dependent pathway. Precisely speaking, only in the virus-producing cell Vif expression is necessary; in its absence, infection of a subsequent target cell terminates at a postentry step through the action of the human APOBEC3G antiviral mechanism. Hf protein has two domains： one binds to APOBEC3G and the other regulates the degradation of APOBEC3G by a conserved sequence, SLQ （Y/F） LA motif. Recently, the research on Vif has also revealed APOBEC3G is a novel component of innate immune system. In fact, APOBEC3G not only acts in DNA editing to block the replication of retroviruses such as HIV-1, but also is able to defend a wide spectrum of distantly related retroviruses and interferes with HBV through a different mechanism from HIE.
