Viral protein U(Vpu) is an accessory protein associated with two main functions important in human immunodeficiency virus type 1(HIV-1) replication and dissemination; these are down-regulation of CD4 receptor through ...Viral protein U(Vpu) is an accessory protein associated with two main functions important in human immunodeficiency virus type 1(HIV-1) replication and dissemination; these are down-regulation of CD4 receptor through mediating its proteasomal degradation and enhancement of virion release by antagonizing tetherin/BST2. It is also well established that Vpu is one of the most highly variable proteins in the HIV-1 proteome. However it is still unclear what drives Vpu sequence variability, whether Vpu acquires polymorphisms as a means of immune escape, functional advantage, or otherwise. It is assumed that the host-pathogen interaction is a cause of polymorphic phenotype of Vpu and that the resulting functional heterogeneity of Vpu may have critical significance in vivo. In order to comprehensively understand Vpu variability, it is important to integrate at the population level the genetic associationapproaches to identify specific amino acid residues and the immune escape kinetics which may impose Vpu functional constraints in vivo. This review will focus on HIV-1 accessory protein Vpu in the context of its sequence variability at population level and also bring forward evidence on the role of the host immune responses in driving Vpu sequence variability; we will also highlight the recent findings that illustrate Vpu functional implication in HIV-1 pathogenesis.展开更多
After infection and integration steps,HIV-1 transcriptions increase sharply and singly-spliced mRNAs are produced.These encode Env (gp120 and gp41) and auxiliary proteins Vif,Vpr and VpU.The same localization within t...After infection and integration steps,HIV-1 transcriptions increase sharply and singly-spliced mRNAs are produced.These encode Env (gp120 and gp41) and auxiliary proteins Vif,Vpr and VpU.The same localization within the unique structure of the mRNAs suggests that the VpU sequence prior to the Env could affect the Env polyprotein expression.The HIV-1 infection process begins when the gp120 subunit of the envelope glycoprotein complex interacts with its receptor(s) on the target cell.The V3 domain of gp120 is the major determinant of cellular co-receptor binding.According to phenotypic information of HIV-1 isolates,sequences from the VpU to V3 regions (119 in R5-and 120 X4-tropic viruses;one per patient) were analysed.The binomial correlation phi coefficient was used to assess covariation among VpU and gp120 V3 signatures.Subsequently,average linkage hierarchical agglomerative clustering was performed.Beyond the classical V3 signatures (R5-viruses:S11,E25D;X4-viruses:S11KR,E25KRQ),other specific V3 and novel VpU signatures were found to be statistically associated with co-receptor usage.Several statistically significant associations between V3 and VpU mutations were also observed.The dendrogram showed two distinct large clusters:one associated with R5-tropic sequences (bootstrap=0.94),involving:(a) H13NP V3,E25D V3,S11 V3,T22A V3 and Q61H VpU,(b) E25A V3 and L12F VpU,(c) D44E VpU,R18Q V3 and D80N VpU ;and another associated with X4-tropic sequences (bootstrap=0.97),involving:(i) E25I V3 and V10A VpU,(ii) 0-1insV VpU,H13R V3,I46L VpU,I30M V3 and 60-62del VpU,(iii) S11KR V3 and E25KRQ V3.Some of these pairs of mutations were encoded always by one specific codon.These data indicate the possible VpU mutational patterns contributing to regulation of HIV-1 tropism.展开更多
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
近来年,抗艾滋病药物新靶点研究为艾滋病药物的开发带来了新希望。以《科学引文索引》(Science Citation Index Expanded,SCI-E)数据库为数据源,利用文献计量分析方法对抗艾滋病药物新靶点从研究热点、国家地区分布、研究机构分布等方...近来年,抗艾滋病药物新靶点研究为艾滋病药物的开发带来了新希望。以《科学引文索引》(Science Citation Index Expanded,SCI-E)数据库为数据源,利用文献计量分析方法对抗艾滋病药物新靶点从研究热点、国家地区分布、研究机构分布等方面进行分析。展开更多
基金Supported by A Grant-in-Aid for Scientific Research from the Ministry of Education,Science,Sports,and Culture(MEXT)of JapanA Grant-in-Aid for AIDS Research from the Ministry of Health,Labor,and Welfare of Japan+1 种基金The Scholarship for the International Priority Graduate Programs,to Hasan Z and Kamori DAdvanced Graduate Courses for International Students(Doctoral Course),MEXT,Japan,to Hasan Z and Kamori D
文摘Viral protein U(Vpu) is an accessory protein associated with two main functions important in human immunodeficiency virus type 1(HIV-1) replication and dissemination; these are down-regulation of CD4 receptor through mediating its proteasomal degradation and enhancement of virion release by antagonizing tetherin/BST2. It is also well established that Vpu is one of the most highly variable proteins in the HIV-1 proteome. However it is still unclear what drives Vpu sequence variability, whether Vpu acquires polymorphisms as a means of immune escape, functional advantage, or otherwise. It is assumed that the host-pathogen interaction is a cause of polymorphic phenotype of Vpu and that the resulting functional heterogeneity of Vpu may have critical significance in vivo. In order to comprehensively understand Vpu variability, it is important to integrate at the population level the genetic associationapproaches to identify specific amino acid residues and the immune escape kinetics which may impose Vpu functional constraints in vivo. This review will focus on HIV-1 accessory protein Vpu in the context of its sequence variability at population level and also bring forward evidence on the role of the host immune responses in driving Vpu sequence variability; we will also highlight the recent findings that illustrate Vpu functional implication in HIV-1 pathogenesis.
文摘After infection and integration steps,HIV-1 transcriptions increase sharply and singly-spliced mRNAs are produced.These encode Env (gp120 and gp41) and auxiliary proteins Vif,Vpr and VpU.The same localization within the unique structure of the mRNAs suggests that the VpU sequence prior to the Env could affect the Env polyprotein expression.The HIV-1 infection process begins when the gp120 subunit of the envelope glycoprotein complex interacts with its receptor(s) on the target cell.The V3 domain of gp120 is the major determinant of cellular co-receptor binding.According to phenotypic information of HIV-1 isolates,sequences from the VpU to V3 regions (119 in R5-and 120 X4-tropic viruses;one per patient) were analysed.The binomial correlation phi coefficient was used to assess covariation among VpU and gp120 V3 signatures.Subsequently,average linkage hierarchical agglomerative clustering was performed.Beyond the classical V3 signatures (R5-viruses:S11,E25D;X4-viruses:S11KR,E25KRQ),other specific V3 and novel VpU signatures were found to be statistically associated with co-receptor usage.Several statistically significant associations between V3 and VpU mutations were also observed.The dendrogram showed two distinct large clusters:one associated with R5-tropic sequences (bootstrap=0.94),involving:(a) H13NP V3,E25D V3,S11 V3,T22A V3 and Q61H VpU,(b) E25A V3 and L12F VpU,(c) D44E VpU,R18Q V3 and D80N VpU ;and another associated with X4-tropic sequences (bootstrap=0.97),involving:(i) E25I V3 and V10A VpU,(ii) 0-1insV VpU,H13R V3,I46L VpU,I30M V3 and 60-62del VpU,(iii) S11KR V3 and E25KRQ V3.Some of these pairs of mutations were encoded always by one specific codon.These data indicate the possible VpU mutational patterns contributing to regulation of HIV-1 tropism.
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.
