Ya-Chi Ho, MD, PhD

As a physician scientist, Dr. Ho investigates viral pathogenesis in the context of genomics, pathophysiology, immunology, and treatment. Specifically, her lab is interested in how chronic viral infection disrupts host homeostasis and causes chronic diseases, including chronic inflammation and cancer.

Dr. Ho's research program focuses on understanding HIV-1 persistence and HIV-1-induced immune dysfunction using single-genome, single-cell, and spatial transcriptomics approaches on clinical samples. She received MD in 2002 (Phi Tau Phi) and completed internal medicine residency and infectious disease fellowship training in Taiwan in 2007. She practiced as an infectious disease attending physician for one year (2007-2008). She received PhD at Johns Hopkins University School of Medicine (Phi Beta Kappa, HHMI International Student Research Fellowship, and Johns Hopkins Young Investigator Award) in 2013, mentored by Dr. Robert F. Siliciano. During PhD, she developed the first HIV-1 full-length single-genome sequencing method that became the standard measurement of the size of the HIV-1 latent reservoir (Cell 2013). As a postdoc, she profiled HIV-1 DNA and RNA landscape and identified the impact of cytotoxic T lymphocytes (CTLs) and defective HIV-1 proviruses on HIV-1 persistence (Cell Host Microbe 2017, Best Paper of the Year, corresponding author). In these two publications, she found that HIV proviruses having defects in packaging signals (Psi) can activate alternative splice site and produce viral proteins.

After she started her lab at Yale University in September 2017, she developed single-cell HIV-1 SortSeq and identified HIV-1-driven aberrant cancer gene expression at the integration site as a mechanism of HIV-1 persistence (Science Translational Medicine 2020). She developed CRISPR-ready HIV-1-infected cell-line models and a dual-reporter drug screen to identify drugs that can suppress HIV-1-induced cancer gene expression (JCI 2020). In addition, her lab (led by postgrad Savannah Pedersen) used a genome-wide CRISPR screen and identified HIV-1 silencing factors including SAFB family proteins and RNA nuclear exosome complex (J Virol 2022). Her lab (led by PhD student Jack Collora) developed HIV-4C and examined HIV-host 3D genome interactions using HiC and HiChIP. We found that HIV interacts with human chromatin in cis (Genome Research 2023).

She is currently working on understanding HIV-1-induced immune dysfunction and clonal expansion dynamics of HIV-1-infected cells using single-cell multi-omic ECCITEseq on clinical samples. In 2022, her lab (led by PhD student Jack Collora) found that HIV-1 preferentially persist in cytotoxic CD4+ T cells, in which a granzyme B inhibitor Serpin B9 helps HIV-infected CD4+ T cells evade immune clearance (Immunity 2022). In 2023, her lab (led by postdoc Yulong Wei) used DOGMAseq to identify the single-cell immune programs of the rare latent and transcriptionally active HIV-infected cells. She found that transcription factor IKZF3 (Aiolos) promotes the proliferation of HIV-infected cells (Immunity 2023). This is the first time in the field that single-cell transcriptional landscape of latently infected cells was uncovered.

In 2025, her lab (led by postdoc Yulong Wei) coupled single-cell DOGMA-seq with TREK-seq on gut samples to capture single-cell ATAC-seq, RNA-seq, 155 surface protein expression, T cell receptor sequence, HIV DNA, and HIV RNA within the same single cell. BACH2 is the leading transcription factor that regulate gut T cell immune responses. BACH2 transcription factor activity is high in gut T cells but not in blood T cells, creating distinct mechanisms of HIV persistence in the blood versus gut. HIV-infected cells in the blood are typically activated, cytotoxic, Th1 effector memory expressing exhaustion molecules. In contrast, HIV-infected cells int the gut are tissue resident memory (TRM) CD4+ T cells having long-lived memory and restrained effector function.

Dr. Ho is a Yale Top Scholar, CSHL Retroviruses Andy Kaplan Prize awardee, Gilead HIV Scholar, and elected member of American Society for Clinical Investigation (ASCI). Dr. Ho's research support mainly comes from NIH, with an R21 funded 1 year after PhD graduation and two R01-level grants funded within one year after she started her lab at Yale University. Investigator for basic science and translational collaboration projects, such as NIH Structural Biology Center CHEETAH, NIH Martin Delaney Collaboratory BEAT HIV and REACH, a U01, and a P01. Her lab is expanding their research program from HIV into T cell fate decisions in the context of diet, chronic inflammation, cancer, and CAR-T cell immunotherapy.