HIV-1 envelope glycoprotein stimulates viral transcription and increases the infectivity of the progeny virus through the manipulation of cellular machinery

Abstract

During HIV infection, large amounts of progeny viral particles, including infectious virus and a large proportion of defective viral particles, are produced. Despite of the critical role of the infectious viruses in infection and pathogenesis in vivo, whether and how those defective viral particles, especially the virus-associated envelope glycoprotein (vEnv), would impact viral infection remains elusive. In this study, we investigated the effect of vEnv on HIV-infected T cells and demonstrated that the vEnv was able to stimulate HIV transcription in HIV-infected cells, including peripheral blood mononuclear cells (PBMCs) isolated from HIV patients. This vEnv-mediated HIV transcription activation is mediated primarily through the interaction between vEnv and CD4/coreceptors (CCR5 or CXCR4). Through transcriptome analysis, we found that numerous cellular gene products involved in various signaling pathways were modulated by vEnv. Among them, we have further identified a cellular microRNA miR181A2, which is downregulated upon vEnv treatment, resulting in increased HIV LTR histone H3 acetylation and HIV transcription. Furthermore, we also found a vEnv-modulated cellular histone deacetylase, HDAC10, whose downregulation is associated with the increased infectivity of progeny viruses. Altogether, these findings provide evidence of the important role vEnv plays in modulating cellular environments and facilitating HIV expression and infection.

Characterization of the Role of Host Cellular Factor Histone Deacetylase 10 during HIV-1 Replication

“…The results showed that HDAC10 transcription was downregulated to 50%, 25%, and 40%, respectively, in different infected individual cells ( Figure 1C upper panel). In summary, these results indicated that the transcription of HDAC10 is down-regulated during HIV-1 replication, which is consistent with our previous results [5].…”

“…The results showed that HDAC10 transcription was downregulated to 50%, 25%, and 40%, respectively, in different infected individual cells ( Figure 1C upper panel). In summary, these results indicated that the transcription of HDAC10 is down-regulated during HIV-1 replication, which is consistent with our previous results [5]. Jurkat cells or C8166 cells were infected with HIV-1 (N119) and collected at 0, 48, and 96 h. The HDAC10 mRNA was detected by quantitative RT-PCR and normalized by house-keeping gene GAPDH while the HDAC10, tubulin, and HIV-1p24 proteins were detected by WB.…”

“…In our previous study, RNA-seq results showed that HIV-1 virion-associated envelope glycoprotein caused the downregulation of endogenous HDAC10. However, except for envelope glycoprotein, whether other viral proteins also directly contribute to this downregulation needs further investigation [5].…”

“…Moreover, HDAC6 has been reported to inhibit HIV-mediated target cell fusion and entry by preventing the acetylation of cortical tubulin and reduce progeny virus infectiousness by preventing Vif-mediated A3G degradation [3,4]. Recently, our studies revealed that another member of the HDAC family, Histone Deacetylases 10 (HDAC10), was downregulated by HIV-1 virion-associated envelope glycoprotein in the HIV-infected cell line J-Lat 6.3 [5]. HDAC10 is a member of the HDAC class II B family [6].…”

Influence of HIV Infection and Antiretroviral Therapy on Bone Homeostasis

“…Soluble HIV-structural proteins are also mediators of cytopathogenic effects. These proteins may act as part of the viral particle or as bystander effect mediators after their release from productively infected cells ( 48 ). Both, p55-gag and gp120 were found to reduce calcium deposition, alkaline-phosphatase activity, levels of secreted BMP-2, -7, and RANKL, as well as the expression and activity of the pro-osteogenic transcription factor runt-related transcription factor 2 (RUNX2) in human osteoblasts.…”