Background:HIV-1 Vpu acts by counteracting the tethering function of tetherin and resulting in the release of HIV-1 virion.Disrupting Vpu-tetherin interactions may provide a promising new target for antiretroviral the...Background:HIV-1 Vpu acts by counteracting the tethering function of tetherin and resulting in the release of HIV-1 virion.Disrupting Vpu-tetherin interactions may provide a promising new target for antiretroviral therapy.Methods:Polypeptides that covered the amino acid sequence on the interface of Vpu-tetherin complex were designed.Phenotypic susceptibilities and cellular toxicities to the polypeptides were measured.The mechanisms of the anti-HIV-1 polypeptides were determined by the Western blot analysis and laser confocal scanning.Seven 20-mer polypeptides from wild-type Vpu amino acid sequence were designed.Results:We report the design and identification of 3 novel anti-HIV-1 polypeptides that derived from Vpu se-quence which can efficiently inhibit HIV-1 infection.A pilot mechanism study showed that the active polypeptide could counteract Vpu-mediated tetherin downregulation.Laser confocal image scanning study showed that the polypeptides bound on the cell surface with a receptor specific binding manner,which may target tetherin that expressed on cell surface.Conclusion:Our work provided first evidence that counteracting Vpu-mediated tetherin downregulation could be a target for novel anti-HIV-1 drug design.Future works to provide direct evidence of inhibitors interact with teth-erin at atomic resolution and the development of small molecules inhibitors targeting Vpu-tetherin interactions may open a new avenue for novel antiretroviral therapy.展开更多
The cellular protein tetherin tethers the HIV-1 viral particles on the cellular membrane to inhibit the replication of HIV-1. However, the HIV-1 accessory protein Vpu counteracts the antiviral function of tetherin. In...The cellular protein tetherin tethers the HIV-1 viral particles on the cellular membrane to inhibit the replication of HIV-1. However, the HIV-1 accessory protein Vpu counteracts the antiviral function of tetherin. In this study, two retroviral vector plasmids were constructed. One inhibited the vpu gene expression; the other one over-expressed the tetherin. Both retroviral vector plasmids could be packaged in the packaging cell line PT67 to obtain the corresponding retroviruses. The retroviral vector plasmids＇ functions of tetherin over-expression or vpu-RNAi were detected at the cell level. Retroviral vector plasmids were transfected to PT67 cells at different ratios from 0T3V to 3TOV, and then mixed retroviruses were harvested. The antiviral functions of mixed retroviruses were detected in HIV-1 infected TZM-bi cells. The results showed that packaged mixed retroviruses could repress the replication of HIV-1 in TZM-bl cells.展开更多
As we venture deeper into space and establish bases and orbital stations on celestial bodies,it is imperative to develop sustainable space transportation methods that minimise propellant usage.Space tethers represent ...As we venture deeper into space and establish bases and orbital stations on celestial bodies,it is imperative to develop sustainable space transportation methods that minimise propellant usage.Space tethers represent one promising option in this endeavour.A space tether,in theory,can operate without the need for any propellant.This paper presents a novel strategy for the use of symmetrical motorised momentum exchange tethers for a 2-way continuous payload transfer system between Earth and Mars.Symmetrical tethers offer the advantage of not necessarily de-orbiting on payload capture and release because there is no change in the geometrical location of the centre of mass when in operation.A novel strategy is proposed requiring 2 tethers,whereby one rotates prograde and the other retrograde,and 2 dummy payloads in suitable parking orbits around each planet to provide overall mass balance.The analysis considers an idealised scenario where planets orbit the Sun in planar,concentric orbits,and no perturbational forces are present,in order to establish the concept.A methodology has been developed to calculate the orbits of the tethers and the dummy payloads around Earth and Mars based on the proposed strategy taking into consideration the reusability of the dummy payloads.A list of possible orbits around Earth and Mars is presented.Additionally,a drag perturbation analysis has been carried out on selected sets of results to determine the orbital decay.Finally,some major failure scenarios are discussed and some recovery options are proposed.展开更多
文摘Background:HIV-1 Vpu acts by counteracting the tethering function of tetherin and resulting in the release of HIV-1 virion.Disrupting Vpu-tetherin interactions may provide a promising new target for antiretroviral therapy.Methods:Polypeptides that covered the amino acid sequence on the interface of Vpu-tetherin complex were designed.Phenotypic susceptibilities and cellular toxicities to the polypeptides were measured.The mechanisms of the anti-HIV-1 polypeptides were determined by the Western blot analysis and laser confocal scanning.Seven 20-mer polypeptides from wild-type Vpu amino acid sequence were designed.Results:We report the design and identification of 3 novel anti-HIV-1 polypeptides that derived from Vpu se-quence which can efficiently inhibit HIV-1 infection.A pilot mechanism study showed that the active polypeptide could counteract Vpu-mediated tetherin downregulation.Laser confocal image scanning study showed that the polypeptides bound on the cell surface with a receptor specific binding manner,which may target tetherin that expressed on cell surface.Conclusion:Our work provided first evidence that counteracting Vpu-mediated tetherin downregulation could be a target for novel anti-HIV-1 drug design.Future works to provide direct evidence of inhibitors interact with teth-erin at atomic resolution and the development of small molecules inhibitors targeting Vpu-tetherin interactions may open a new avenue for novel antiretroviral therapy.
基金National Natural Science Foundation of China(81101245,30970162)The Fundamental Research Funds for the Central Universities(65011871)National Training Programs of Innovation for Undergraduates(111005505)
文摘The cellular protein tetherin tethers the HIV-1 viral particles on the cellular membrane to inhibit the replication of HIV-1. However, the HIV-1 accessory protein Vpu counteracts the antiviral function of tetherin. In this study, two retroviral vector plasmids were constructed. One inhibited the vpu gene expression; the other one over-expressed the tetherin. Both retroviral vector plasmids could be packaged in the packaging cell line PT67 to obtain the corresponding retroviruses. The retroviral vector plasmids＇ functions of tetherin over-expression or vpu-RNAi were detected at the cell level. Retroviral vector plasmids were transfected to PT67 cells at different ratios from 0T3V to 3TOV, and then mixed retroviruses were harvested. The antiviral functions of mixed retroviruses were detected in HIV-1 infected TZM-bi cells. The results showed that packaged mixed retroviruses could repress the replication of HIV-1 in TZM-bl cells.
基金the funding provided by the University of Strathclyde。
文摘As we venture deeper into space and establish bases and orbital stations on celestial bodies,it is imperative to develop sustainable space transportation methods that minimise propellant usage.Space tethers represent one promising option in this endeavour.A space tether,in theory,can operate without the need for any propellant.This paper presents a novel strategy for the use of symmetrical motorised momentum exchange tethers for a 2-way continuous payload transfer system between Earth and Mars.Symmetrical tethers offer the advantage of not necessarily de-orbiting on payload capture and release because there is no change in the geometrical location of the centre of mass when in operation.A novel strategy is proposed requiring 2 tethers,whereby one rotates prograde and the other retrograde,and 2 dummy payloads in suitable parking orbits around each planet to provide overall mass balance.The analysis considers an idealised scenario where planets orbit the Sun in planar,concentric orbits,and no perturbational forces are present,in order to establish the concept.A methodology has been developed to calculate the orbits of the tethers and the dummy payloads around Earth and Mars based on the proposed strategy taking into consideration the reusability of the dummy payloads.A list of possible orbits around Earth and Mars is presented.Additionally,a drag perturbation analysis has been carried out on selected sets of results to determine the orbital decay.Finally,some major failure scenarios are discussed and some recovery options are proposed.
