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The role of high mobility group AT- hook 1 (HMGA1) gene expression in HIV reactivation

  • Author(s): Abewe, Hosiana
  • Advisor(s): Richman, Douglas
  • et al.
Abstract

In the present era of combination anti-retroviral therapy (ART), the latent cellular reservoir of HIV is recognized as the major barrier to a cure. HIV latency may be reversed by a controlled induction of virus reactivation in the presence of ART to reveal latently infected cells for immune system recognition and destruction. Histone deacetylase inhibitors (HDACis) have been used as potential latency reversing agents for HIV. Suberoylanilide hydroxamic acid (SAHA), the most widely tested HDACi, has effectively induced expression of HIV RNA in patients on suppressive ART, but has failed to reduce the size of the latent reservoir. The secondary effects of SAHA on host gene and protein expression are among the possible explanations of why SAHA has failed to deplete the latent reservoirs. SAHA upregulates the high mobility group AT-hook 1 (HMGA1) gene, which encodes a protein that represses reporter transcription from HIV promoter, long terminal repeat (LTR) in primary CD4 T cells. In this thesis study, we investigated the role of HMGA1 in HIV reactivation by SAHA. Latently infected CD4 T cells from 11 different blood donors were generated through in vitro model of HIV latency and were each treated with 1uM SAHA or its solvent dimethyl sulfoxide (DMSO). The expression of HMGA1 and HIV reactivation were assessed using droplet digital PCR (ddPCR). The degree of HMGA1 upregulation by SAHA negatively correlated with levels of HIV reactivation. Knockdown experiments were conducted using GapmeR technology in primary CD4 T cells. HMGA1 GampeRs were used to test whether HMGA1 played a role in HIV reactivation by SAHA. Latently infected CD4 T cells from 5 seronegative blood donors were generated through in vitro model of HIV latency and were each treated with 1 uM SAHA or DMSO. The expression of HMGA1 and HIV multiply spliced transcripts was measured using ddPCR. Although, a modest knockdown of HMGA1 was achieved, the improvement of HIV reactivation by SAHA in three samples suggested that HMGA1 presents a potential target for improvement of HIV reactivation by SAHA. However, further studies that optimize HMGA1 knockdown are needed to fully understand the role of HMGA1 in HIV reactivation by SAHA.

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