Ya-Chi Ho Lab

The primary goal of the Ho Lab is to investigate the impact of viral pathogenesis on human health. We investigate viral pathogenesis in the context of genomics, pathophysiology, immunology, and treatment. Specifically, we are interested in how chronic viral infection disrupts host homeostasis and causes chronic diseases, including chronic inflammation and cancer. Our approach involves using advanced molecular biology, genomics, immunology, single-cell multi-omics, spatial transcriptomics, bioinformatics tools on clinical samples and animal models.

HIV integrates into the DNA of the infected cells as an integrated HIV provirus. Despite effective antiretroviral therapy, these HIV-infected cells persist lifelong. Although only a very small proportion of blood CD4+ T cells harbor infectious HIV (<0.1%), the millions of HIV-infected cells establish the HIV latent reservoir as early as 3 days post infection and persist lifelong. Using single-cell multiomics and spatial transcriptomics, we identify the rare HIV-infected cells in blood and tissues, primarily the lymph nodes and the gut. We investigate how these rare HIV-infected cells take advantage of the host immune system, evade immune clearance, and persist lifelong. In tissues, there are immune sanctuary sites where immune cells cannot enter, allowing HIV-infected cells to persist. Similarly, in the tumor microenvironment, there are immune excluded regions ("cold tumor") in the tumor nest where immune cells cannot enter, allowing tumor to persist. Using single-cell multiomics, spatial transcriptomics (with HIV-specific probes), and mouse models, we are dissecting how HIV-infected cells and cancer evade immune clearance.

T lymphocyte cell fate decisions, including differentiation, migration, effector function, tissue residency, and proliferation, are governed by key transcription factors, local cytokine cues, and cell-cell communications. Dysregulation of T cell homeostasis leads to pathogenic inflammation and impaired immunity against infection and cancer. Advancement in single-cell multi-omic profiling enabled characterization of heterogeneous T cell populations and immune responses in normal physiology and disease conditions. Understanding and targeting upstream regulators of immune dysfunction will advance immunotherapies for human diseases, such as CAR-T cell therapy for cancer. For example, we found high BACH2 transcription factor activity in the gut, but not in the blood. BACH2 serves as the effector-to-memory molecular switch that turns off effector function in gut T cells. We are investigating the upstream drivers of high BACH2 activity in the gut.

HIV integrates into the genome of infected cells. These infected cells persist lifelong. ART cannot kill HIV-infected cells. HIV integration into host genes induces aberrant HIV-to-host RNA splicing, driving aberrant cancer gene expression. In parallel, HIV-induced chronic inflammation leads to higher mutation rates in hematopoietic stem cells, causing higher incidence of clonal hematopoiesis in people with HIV. Using paired single-cell multi-omics and long-read sequencing, we are investigating the normal and aberrant T cell clonal expansion during HIV infection.

Dr. Ho defines HIV reservoir by single-genome near-full length HIV proviral sequencing when she was a PhD student in Dr. Rober F. Siliciano’s lab (Cell 2013). She is among the first to describe that HIV proviral sequences serve as a footprint of cytotoxic T lymphocyte (CTL) selection pressure (Cell Host Microbe 2017, in collaboration with Dr. Brad Jones). She is among the first who discovered that HIV proviruses having packaging signal (ψ) defects can activate cryptic RNA splice donors and produce viral proteins (Cell 2013, Cell Host Microbe 2017).

The Ho Lab pioneers cutting-edge single-cell multi-omic profiling of HIV reservoir. The HIV-infected cells are extremely rare (<0.1% of CD4+ T cells) in the blood from people living with HIV under suppressive antiretroviral therapy. She used HIV RNA Flow-FISH to sort HIV-infected cells for single-cell RNA-seq (Science Translational Medicine 2020). She then pioneered profiling of HIV-infected cells in their in vivo states without ex vivo stimulation using ECCITE-seq (Immunity 2022), DOGMA-seq (Immunity 2023), and DOGMA-seq + TREK-seq (Immunity 2025). The Ho lab publishes the first studies in the field capturing the single-cell transcriptome and immune profiles of both transcriptionally active and latent HIV in the blood and the gut.