Cholesterol-25-hydroxylase(CH25 H)is a membrane protein associated with endoplasmic reticulum,and it is an interferon-stimulated factor regulated by interferon.CH25 H catalyzes cholesterol to produce 25-hydroxycholest...Cholesterol-25-hydroxylase(CH25 H)is a membrane protein associated with endoplasmic reticulum,and it is an interferon-stimulated factor regulated by interferon.CH25 H catalyzes cholesterol to produce 25-hydroxycholesterol(25 HC)by adding a second hydroxyl to the 25 th carbon atom of cholesterol.Recent studies have shown that both CH25 H and 25 HC could inhibit the replication of many viruses.In this study,we found that ectopic expression of CH25 H in HEK-293 T and BHK-21 cell lines could inhibit the replication of Seneca Valley virus(SVV)and that there was no species difference.On the other hand,the knockdown of CH25 H could enhance the replication of SVV in HEK-293 T and BHK-21 cells,indicating the importance of CH25 H.To some extent,the CH25 H mutant without hydroxylase activity also lost its ability to inhibit SVV amplification.Further studies demonstrated that 25 HC was involved in the entire life cycle of SVV,especially in repressing its adsorption process.This study reveals that CH25 H exerts the advantage of innate immunity mainly by producing 25 HC to block virion adsorption.展开更多
Cholesterol-25-hydroxylase(CH25 H)and its enzymatic product 25-hydroxy cholesterol(25 HC)exert broadly antiviral activity including inhibiting HIV-1 infection.However,their antiviral immunity and therapeutic efficacy ...Cholesterol-25-hydroxylase(CH25 H)and its enzymatic product 25-hydroxy cholesterol(25 HC)exert broadly antiviral activity including inhibiting HIV-1 infection.However,their antiviral immunity and therapeutic efficacy in a nonhuman primate model are unknown.Here,we report that the regimen of 25 HC combined with antiretroviral therapy(ART),provides profound immunological modulation towards inhibiting viral replication in chronically SIVmac239-infected rhesus macaques(RMs).Compared to the ART alone,this regimen more effectively controlled SIV replication,enhanced SIVspecific cellular immune responses,restored the ratio of CD4/CD8 cells,reversed the hyperactivation state of CD4^(+)T cells,and inhibited the secretion of proinflammatory cytokines by CD4^(^(+))and CD8^(+)T lymphocytes in chronically SIVinfected RMs.Furthermore,the in vivo safety and the preliminary pharmacokinetics of the 25 HC compound were assessed in this RM model.Taken together,these assessments help explain the profound relationship between cholesterol metabolism,immune modulation,and antiviral activities by 25 HC.These results provide insight for developing novel therapeutic drug candidates against HIV-1 infection and other related diseases.展开更多
基金supported by the National Natural Science Foundation of China(31772749,31572495)the Fundamental Research Funds for the Central Universities(2662017PY108)Natural Science Foundation of Hubei Province(2019CFA010)。
文摘Cholesterol-25-hydroxylase(CH25 H)is a membrane protein associated with endoplasmic reticulum,and it is an interferon-stimulated factor regulated by interferon.CH25 H catalyzes cholesterol to produce 25-hydroxycholesterol(25 HC)by adding a second hydroxyl to the 25 th carbon atom of cholesterol.Recent studies have shown that both CH25 H and 25 HC could inhibit the replication of many viruses.In this study,we found that ectopic expression of CH25 H in HEK-293 T and BHK-21 cell lines could inhibit the replication of Seneca Valley virus(SVV)and that there was no species difference.On the other hand,the knockdown of CH25 H could enhance the replication of SVV in HEK-293 T and BHK-21 cells,indicating the importance of CH25 H.To some extent,the CH25 H mutant without hydroxylase activity also lost its ability to inhibit SVV amplification.Further studies demonstrated that 25 HC was involved in the entire life cycle of SVV,especially in repressing its adsorption process.This study reveals that CH25 H exerts the advantage of innate immunity mainly by producing 25 HC to block virion adsorption.
基金supported by the National Natural Science Foundation of China(81971927,31870912,32000124)the National Science and Technology Major Project of China(2018ZX10731101-002)+4 种基金the National Key Research and Development Program of China(2018YFA0900803)the Science and Technology Planning Project of Shenzhen City(20190804095916056,JCYJ20200109142601702)the High Level Project of Medicine in Longhua,Shenzhen(HLPM201907020105)China Postdoctoral Science Foundation(Grant No.2019M663140)the Municipal Health and Medical cooperation innovation Major Project of Guangzhou City(201704020219,201803040002)。
文摘Cholesterol-25-hydroxylase(CH25 H)and its enzymatic product 25-hydroxy cholesterol(25 HC)exert broadly antiviral activity including inhibiting HIV-1 infection.However,their antiviral immunity and therapeutic efficacy in a nonhuman primate model are unknown.Here,we report that the regimen of 25 HC combined with antiretroviral therapy(ART),provides profound immunological modulation towards inhibiting viral replication in chronically SIVmac239-infected rhesus macaques(RMs).Compared to the ART alone,this regimen more effectively controlled SIV replication,enhanced SIVspecific cellular immune responses,restored the ratio of CD4/CD8 cells,reversed the hyperactivation state of CD4^(+)T cells,and inhibited the secretion of proinflammatory cytokines by CD4^(^(+))and CD8^(+)T lymphocytes in chronically SIVinfected RMs.Furthermore,the in vivo safety and the preliminary pharmacokinetics of the 25 HC compound were assessed in this RM model.Taken together,these assessments help explain the profound relationship between cholesterol metabolism,immune modulation,and antiviral activities by 25 HC.These results provide insight for developing novel therapeutic drug candidates against HIV-1 infection and other related diseases.
