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Investigations of HIV Latency Through Transcriptomic and Proteomic Profiling


The human immunodeficiency virus (HIV) has been a global threat for over three decades despite treatments, preventative measures, and public awareness. HIV hides from the immune system by entering a latent state within CD4 T-cells and removal of therapy results in a resurgence of infection. Therapies to combat HIV were designed to shock the virus from latency and kill infected cells, i.e. "Shock and Kill", and are often studied in cell models due to the paucity of infected cells and no method to isolate them from HIV infected individuals. Transcriptomic and proteomic methods have proven key to studying HIV latency and demonstrate methods by which the "Shock and Kill" strategy may be improved for HIV eradication.

First, two RNA-Seq studies of models of HIV latency are presented (Chapters 2 and 3). Through host transcriptome analysis in the "Bosque and Planelles TCM model of HIV latency", it was demonstrated that host gene expression was reflective of the response to active instead of latent infection. It was shown that fully infectious virus was reconstituted through recombination between the deficient HIV construct and pLET-LAI plasmid. Analysis of host and virus transcripts in the refined "Martins et al." model, demonstrated it represented a form of latency. Furthermore, genes relating to p53 signaling were dysregulated and inhibition of p53 resulted in reduction of the total percentage of latently infected cells.

Next, the effect of the histone deacetylase inhibitor SAHA, a latency reversing agent, was analyzed (Chapters 4 and 5). This revealed SAHA dysregulated genes in a way that was counterproductive to HIV reactivation. Furthermore, analysis of HERV elements dysregulated by SAHA demonstrated elements from multiple families were upregulated with a specificity for those from LTR12.

In summary, this work demonstrated the importance of transcriptomic and proteomic analysis to the study of HIV latency models, led to a revision of the first model, and the importance of the p53 signaling in latency for the second. This work also demonstrated the effect of SAHA treatment on CD4 T-cells, which may potentially explain why SAHA has proven somewhat ineffective in clinical trials to reactivate HIV from latency.

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