Abstract
Following human immunodeficiency virus type 1 (HIV-1) integration into host cell DNA, the viral promoter can become transcriptionally silent in the absence of appropriate signals and factors. HIV-1 gene expression is dependent on regulatory elements contained within the long terminal repeat (LTR) that drive the synthesis of viral RNAs and proteins through interaction with multiple host and viral factors. Previous studies identified single nucleotide polymorphisms (SNPs) within CCAAT/enhancer binding protein (C/EBP) site I and Sp site III (3T, C-to-T change at position 3, and 5T, C-to-T change at position 5 of the binding site, respectively, when compared to the consensus B sequence) that are low affinity binding sites and correlate with more advanced stages of HIV-1 disease. Stably transfected cell lines containing the wild type, 3T, 5T, and 3T5T LTRs were developed utilizing bone marrow progenitor, T, and monocytic cell lines to explore the LTR phenotypes associated with these genotypic changes from an integrated chromatin-based microenvironment. Results suggest that in nonexpressing cell clones LTR-driven gene expression occurs in a SNP-specific manner in response to LTR activation or treatment with trichostatin A treatment, indicating a possible cell type and SNP-specific mechanism behind the epigenetic control of LTR activation.
Highlights
Over the past decade, targeting the viral entry process, reverse transcriptase, integrase, and protease with highly active antiretroviral therapy (HAART) has prolonged the lives of people infected with human immunodeficiency virus type 1 (HIV-1)
HE-GFP long terminal repeat (LTR) are induced much more efficiently with the introduction of cytokines and as such were used as a control to show that the LTR was able to be induced
We have previously demonstrated and identified specific single nucleotide polymorphisms (SNPs) within CCAAT/enhancer binding protein (C/EBP) site I (3T) and Sp site III (5T) that correlate with increased HIV-1 disease severity, HIV-1-associated dementia (HAD), as well as altered transcription factor binding to those sites [23, 24, 26, 37, 38]
Summary
Over the past decade, targeting the viral entry process, reverse transcriptase, integrase, and protease with highly active antiretroviral therapy (HAART) has prolonged the lives of people infected with HIV-1. Through various avenues such as cessation of highly active antiretroviral therapy (HAART), the development of drug resistance, and replication of virus in compartments refractile to drug penetration, expansion of HIV-1 viremia or emergence of specific genetic viral variants may rebound from latent reservoirs such as bone marrow progenitor cells, monocytes, and resting memory T cells within the host and repopulate the resident immune and other cellular compartments present in end organs penetrated during the course of HIV disease [1,2,3]. It has recently been shown that infected bone marrow progenitor cells can differentiate into both monocytes and T cells [1], potentially serving as a source of HIV-1-infected macrophages and T cells, and they play a critical role in neuroinvasion and progression of CNS disease
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