Molecular Mechanism Of HIV-1 Induced MiR-33b-5p Targeted Down-regulation Of ABCA1 And Cholesterol Metabolism Disorders

Human immunodeficiency virus type 1(HIV-1)is a retrovirus that causes acquired immune deficiency syndrome(AIDS).HIV-1 is one of the most serious threats to global public health security.Antiretroviral therapy(ART)can effectively control virus replication,improve immune status,significantly reduce the incidence and mortality of HIV-1 patients,and effectively prolong patients’ lives and reduce virus spread.The low level of viral replication and drug side effects might result in the HIV/AIDS related disease incidence increasing year by year,which has a serious impact on the health of HIV-1-infected people.For example,the incidence of cardiovascular disease and metabolic syndrome increasing than age-matched uninfected people,while abnormal lipid metabolism is the leading cause of cardiovascular and cerebrovascular diseases,however the relationship between viral infection and lipid metabolism remains unknown.Mi RNAs play an important role in virus-host interactions.In this study,we used miRNA as a clue to investigate the effect of HIV-1 infection and host.We used miRNA chips to detect and analyze the significantly up-regulated or down-regulated miRNAs in pserdotyped HIV-1 infected T cell line MT-4 cells.We investigated the effect mechanism of HIV-1 infection on lipid metabolism via miRNA regulation using databases and infection experiments.First,we performed miRNA microarray analysis in MT4 cells infected with HIV-1 pseudovirus and discovered that viral infection could cause an increase or decrease in the expression of miRNAs,the miR-33b-5p was the most up-regulated and reproducible.In MT4 cells,miR-33b-5p was found to be dependent on HIV-1concentration or infection time.Mi R-33b-5p levels were significantly higher in HIV-1infected patients than uninfected patients.According to the findings,HIV-1 infection can significantly increase the expression of miR-33b-5p.The target gene of miR-33b-5p was then identified using database analysis and fluorescence reporter expression experiments.The findings suggested that ABCA1 could be a target gene for miR-33b-5p.Further infection revealed that ABCA1 was also reduced in HIV-1 infected cells,and the addition of a miR-33b-5p inhibitor can reverse the reduction of ABCA1.These findings suggested that HIV-1 infection suppresses ABCA1 expression by increasing miR-33b-5p levels.We hypothesized that because ABCA1 is a key regulator of lipid metabolism,HIV-1 infection might affect lipid metabolism by affecting ABCA1.We also looked at the lipid levels in HIV-1-infected THP-1/PMA macrophages because macrophages are the main cells responsible for lipid metabolism in the blood and are also HIV-1 target cells.The results showed that cholesterol and triglycerides accumulated in HIV-1 infected cells,and their amount in the supernatant was significantly reduced.These findings suggested that HIV-1 infection disrupts cholesterol metabolism by increasing miR-33b-5p expression and suppressing ABCA1 expression.This study provides evidence that HIV-1 infection can affect the host’s lipid metabolism and may be one of the causes of cardiovascular and cerebrovascular diseases,as well as metabolic syndrome with abnormal lipid metabolism in virus-infected individuals.