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Finding a cure for HIV

- A molecular virology approach

Despite effective antiretroviral therapy, HIV persists as an integrated provirus. These HIV-infected cells are resistant to immune clearance and antiretroviral therapy. Upon treatment interruptions, viral rebound will resume. Therefore, all HIV-infected individuals need to take life-long antiretroviral therapy. Given the adverse effects, drug resistance and economical burden of lifelong antiretroviral therapy, a cure is needed to control the global HIV endemic.

The mission of the Ho lab is to understand HIV persistence and find a cure for HIV infections. The scientific goal is to understand how HIV persists in cells, particularly CD4 T lymphocytes, and whether epigenetic silencing can permanently and irreversibly silence HIV expression. We use a molecular virology approach to examine mechanisms of HIV persistence using blood samples from HIV-infected individuals.

1. Understanding how HIV-host interactions, one cell at a time: using single-cell HIV SortSeq for HIV viral genome landscapes and transcriptome analysis

Understanding HIV persistence in cells from HIV-infected individuals is challenging because of the rarity of HIV-infected cells (only 1-10 per million CD4 T cells contain infectious HIV, while 100-1000 per million CD4 T cells contain defective HIV) and the lack of specific markers which can distinguish HIV-infected cells from uninfected cells. Using RNA-preserving single-cell RNAseq of HIV-infected cells harboring inducible HIV, we examine the HIV and host gene expression at a single cell level to understand how HIV reactivation changes the host cellular environment.

2. Block-and-lock: identification of HIV epigenetic silencing agents for a drug-free, virus-free remission or "functional cure"

Despite the presence of many classes of antiretroviral therapy, the HIV promoter LTR is left active and untreated. HIV expression causes chronic immune activation and viral rebound. We propose to identify HIV epigenetic silencing agents which can permanently and irreversibly repress HIV transcription, similar to how human endogenous retroviruses are silenced. Using a high-throughput drug screening, we are working on identification of HIV epigenetic silencing agents which can preferentially silence HIV expression without affecting host gene expression.

Single-cell transcriptional landscapes reveal HIV-1–driven aberrant host gene transcription as a potential therapeutic target

HIV SortSeq identified the rare HIV-infected cells and a new way to treat HIV. See our "Single-cell transcriptional landscapes reveal HIV-1–driven aberrant host gene transcription as a potential therapeutic target" published on May 13, 2020 at Science Translational Medicine.
1. We developed HIV-1 SortSeq which uses HIV RNA expression as a surrogate to identify HIV-infected cells. This RNA-preserving method enables single-cell RNAseq on formaldehyde fixed samples.
2. HIV RNA positive cells are enriched in genes related to RNA processing and viral gene expression.
3. When HIV integrates into a host gene, HIV dominates over the host promoter and drives aberrant cancer gene expression by splicing from HIV into the host RNA.

Targeting RNA processing and T cell activation halts HIV-1-driven aberrant host-transcription

We identified drugs which may suppress HIV-induced immune activation and the expansion of the HIV latent reservoir. See our manuscript at in-press preview "Filgotinib suppresses HIV-1-driven gene transcription by inhibiting HIV-1 splicing and T cell activation" published on June 23, 2020 at Journal of Clinical Investigation.
1. We used a drug screen on a dual-reporter cell line to identify drugs which can suppress HIV expression without affecting cellular gene expression.
2. We identified 16 cellular pathways and 11 FDA-approved drugs which can suppress HIV expression.
3. Using transcriptome landscape analysis, we found that HIV-suppressing agents, such as the JAK inhibitor filgotinib, can inhibit HIV-driven cancer gene expression at the HIV integration site.
4. Using differential expression analysis (Ingenuity Pathway Analysis, IPA) and gene-set enrichment analysis (GSEA), we identified T cell activation and RNA processing-related genes that mediates HIV suppression.
5. Using intron retention analysis, we found a new function of filgotinib as a splice inhibitor.
6. Using limiting dilution culture of CD4+ T cells from HIV-infected individuals, we found that treating cells with HIV-suppressing agents can reduce the proliferation of HIV-infected cells ex vivo.

CFAR Seminar June 2018 Ya-Chi Ho MD, PhD