Mechanism On The Stimulation Of HIV-1Transcription And Replication Regulated By HCV NS3/4A Complex

Human immunodeficiency virus (HIV) is a deadly bloodborne pathogen to human health. Sharing the same routes of transmission, hepatitis C virus (HCV) is frequently detected from HIV-infected patients. It has been clinically demonstrated that co-infection of HCV aggravates the manifestation of HIV and complicates the treatment of the patients. In this study, HIV-1fully infectious proviral clone NL4-3transfected human hepatoma Huh7cells were infected with HCVlb strain to establish an in vitro co-infection model. Results showed that viral loads between HCV input and HIV-1output were closely associated (R=0.978, p<0.05) and HIV-1replication was significantly enhanced by HCV infection. Analysis of individual HCV proteins revealed that NS3/4A complex and NS3but not NS4A protein within the complex up-regulated HIV-1replication. We demonstrated that NS3stimulated HIV-1replication and5’-LTR activation through NF-κB pathway, while the entire NS3/4A complex could only activate the same stimulation if HIV-1Vpu protein was present. The mutual impairment of their stability by NS3/4A and Vpu supported the hypothesis that HIV-1replication was stimulated by the activation of NF-κB pathway, following association between HIV-1Vpu protein and HCV NS3/4A complex. These results provided new insights in the molecular interactions between HIV-1/HCV co-infection and potential targets to develop new therapy.