Study On The Metabolism Disorders In HIV-1-infected Patients And Damage Of Endothelial Cells By Related Proteins

ObjectivesHuman immunodeficiency virus(HIV)establishes a chronic infection finally leading to acquired immunedeficiency syndrome(AIDS),which is characterized by the onset of opportunistic infections and tumors.The widespread introduction of antiretroviral therapy has resulted in a shift in causes of mortality from AIDS-defining illnesses to non-AIDS-defining illnesses such as endocrine abnormalities,metabolism disorders,cardiovascular diseases,osteoporosis,neurocognitive disorders and nonAIDS-defining cancers.In this study,we focused on metabolic abnormalities such as thyroid dysfunction,hyperglycemia and hyperlipidemia of HIV-1-infected patients.Besides,we explored the possible mechanisms by which regulatory protein Tat,envelope protein gp120 and oxidized low-density lipoprotein(ox LDL)promote cardiovascular disease by impairing endothelial cells(ECs)functions.Methods1)178 cases of HIV-1-infected patients were included and divided into ART group and ART-naive group according to whether they had received ART.The incidence of thyroid dysfunction,relationship between thyroid hormone levels and HIV-1 infection and ART were analyzed.2)First,a cross-sectional study including 180 HIV-1-infected patients was conducted to analyze the incidence of impaired fasting glucose(IFG)and diabetes mellitus(DM),compare blood lipid and abnormal immune activation levels of different glucose metabolism groups as well as evaluate predictors of abnormal glucose metabolism.Then a retrospective study was conducted to further analyze the change of total cholesterol(TC)levels in ART group and the relationship between TC levels,glucose metabolism,HIV-1 infection and ART within 6 years since initiation of ART.3)Transcriptome sequencing was performed to to explore the impairment of primary endothelial cells(ECs)function after stimulation of Tat,gp120 and ox LDL.Results1)33.1%(59/178)of the patients included were diagnosed as thyroid dysfunction,mostly hypothyroidism.Thyroid dysfunction was significantly more frequent in the ART group(41/104,39.4%)than in the ART-naive group(18/74,24.3%;P < 0.05).2)In the cross-sectional study,IFG and DM were significantly more frequent in the ART group than in the ART-naive group(57.8% vs 48.1%,P<0.05;19.4% vs 7.4%,P<0.05).Among patients under ART,serum levels of triglycerides,very low-density lipoprotein cholesterol and CD8+ HLA-DR+ T cells counts were higher in IFG and DM patients than in euglycemic patients(P<0.05).In the retrospective study,TC levels of patients diagnosed with DM were significantly higher than those with euglycemia 2 and 4 years after initiation of ART(P<0.05).Linear mixed-effect model demonstrated that disturbance of glucose metabolim and CD4+ cell counts were positively correlated with TC levels after initiation of ART.3)Transcriptome sequencing revealed that Tat,gp120 and ox LDL could down-regulate the expression of COL4A1,COL4A2 and HSPG2 of ECs,as well as up-regulate the expression of MMP1,ET1 of ECs;gp120 and ox LDL could down-regulate the expression of TGFB1 of ECs,as well as up-regulate the expression of CXCL8,IL6,F2RL1 and EGR1 of ECs;ox LDL could down-regulate the expression of NOS3 of ECs,as well as upregulate the expression of CD99 and PECAM1 of ECs.All the changes in gene expression may promote the occurrence and development of AS.Conclusions1.Thyroid dysfunction is more frequent in HIV-1-infected patients,especially those who under ART,mainly manifested as hypothyroidism.2.ART can induce dysglycemia and dyslipidemia in HIV-1-infected patients.Dysglycemia is associated with dyslipidemia in patients3.Tat,gp120 and ox LDL may promote the development of AS by impairing ECs.