Book Description

HIV envelope glycoprotein, composed of gp41 and gp120 subunits, is a key viral protein in HIV infection and replication. The role of HIV envelope glycoprotein in viral entry and membrane fusion has been well studied. However, how HIV envelope glycoprotein modulates downstream gene expression to enhance viral replication and the underlying mechanism of this action are poorly understood. In order to better understand the role of HIV envelope glycoprotein in HIV expression and pathogenesis, my study focused on the characterization and role of the virion-associated envelope glycoprotein (vEnv) in viral transcription of HIV infected cells. My results showed that the vEnv binding to CD4 receptor and coreceptor (CCR5 or CXCR4) activates HIV transcription in HIV infected CD4+ T lymphocytes, including HIV infected cell lines and peripheral blood mononuclear cells (PBMCs) isolated from HIV aviremic patients. Through transcriptome analysis, I found that numerous cellular gene products modulated by vEnv were involved in various signaling pathways, including cellular transcription, T cell receptor signaling, cell cycle, and actin skeleton organization. Among these modulated genes, I further identified a cellular microRNA, microRNA 181A2 (miR-181A2), which is associated with the transcriptional activation by vEnv. My results revealed that miR-181A2 is downregulated upon vEnv treatment, resulting in an increase of cellular p300/CBP associated factor (PCAF) expression, thereby allowing an increased HIV LTR histone H3 acetylation and HIV transcriptional activation. Further, I also identified another vEnv-modulated cellular gene, histone deacetylase 10 (HDAC10), which is related to viral replication. The results showed the downregulation of HDAC10 benefits viral replication through promoting viral integration. Furthermore, the co-immunoprecipitation assay demonstrated that HDAC10 interacts with viral integrase by binding to integrase amino acid 55-165. Interestingly, this interaction does not alter the lysine acetylation state of integrase but specifically decreases the binding of HIV integrase to host factor LEDGF/p75, which leads to the inhibition of viral integration. In addition to regulating viral integration, the results also revealed that the progeny viral infectivity is inversely correlated with cellular HDAC10 level. In conclusion, this thesis revealed the function of vEnv during HIV replication and provided new potential targets for HIV therapy.