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.
An overview of Dr. Ho's work presented at the UW/Fred Hutch Center for AIDS Research (CFAR):