Ya-Chi Ho, MD, PhD
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Research Summary
Despite effective antiretroviral therapy (ART), HIV persists in latently infected cells which is the major barrier to cure. Interruption in ART inevitably leads to viral rebound, and life-long ART is required for HIV-infected individuals. The goal of the Ho lab is to use molecular virology, T cell biology, genomics and single cell technology to understand mechanisms of HIV persistence and to develop HIV cure strategies. Using clinical samples from HIV-infected individuals, our translational approach may expedite the application of basic research into clinical uses.
Extensive Research Description
Single-cell multi-omics understanding of HIV-induced immune dysfunction
The goal of the Ho lab is to exploit molecular virology, genetics, bioinformatics, immunology and single-cell technology to understand the mechanisms of HIV persistence and develop a cure for HIV. In particular, we use blood samples from HIV-infected individuals to interrogate HIV-host interactions ex vivo. Our translational approach bridges bench discoveries into clinical applications. Rotation projects are available from wet-bench virology/immunology experiments to computational and bioinformatic analyses on single-cell transcriptome, depending on the interest of the student.
HIV persistence in clonally expanding CD4+ T cells is the major barrier to cure. Studying HIV-infected cells in clinical samples has been challenging, due to the rarity, heterogeneity, and lack of cellular markers for HIV-infected cells. Using paired blood samples during viremia and after suppressive ART from a randomized and interventional clinical trial (Sabes study), we interrogated how immediate versus delayed ART affected HIV-induced immune dysfunction and HIV persistence. By capturing surface protein expression, cellular transcriptome, HIV RNA, and T cell receptor sequencing within the same single cells, we identified the clonal expansion dynamics of T cell clones harboring HIV and the transcriptional program driving HIV persistence and T cell proliferation.
Using genomics approach to understand mechanisms of HIV persistence and latency
HIV persists in the latent reservoir as the major barrier to cure. The size of the latent reservoir may increase through clonal expansion. Only 1-10 per million CD4+ T cells contain infectious HIV, and there is no reliable marker which can identify HIV-infected cells from HIV-infected patients for molecular characterization. We developed HIV SortSeq to identify HIV-infected cells from HIV-infected patients for single-cell RNAseq. We found that HIV promotes the survival of the infected cells through induction of aberrant transcription of cancer-related genes.
Coauthors
Research Interests
Genetics; HIV; Immunotherapy; Microbiology; Host-Pathogen Interactions; Transcriptome; Epigenetic Repression
Public Health Interests
HIV/AIDS
Research Image
2021 June lab photo on Zoom
Selected Publications
- Inhibition of a Chromatin and Transcription Modulator, SLTM, Increases HIV-1 Reactivation Identified by a CRISPR Inhibition ScreenPedersen SF, Collora JA, Kim RN, Yang K, Razmi A, Catalano AA, Yeh YJ, Mounzer K, Tebas P, Montaner LJ, Ho YC. Inhibition of a Chromatin and Transcription Modulator, SLTM, Increases HIV-1 Reactivation Identified by a CRISPR Inhibition Screen. Journal Of Virology 2022, 96: e00577-22. PMID: 35730977, PMCID: PMC9278143, DOI: 10.1128/jvi.00577-22.
- Single-cell multiomics reveals persistence of HIV-1 in expanded cytotoxic T cell clonesCollora JA, Liu R, Pinto-Santini D, Ravindra N, Ganoza C, Lama JR, Alfaro R, Chiarella J, Spudich S, Mounzer K, Tebas P, Montaner LJ, van Dijk D, Duerr A, Ho YC. Single-cell multiomics reveals persistence of HIV-1 in expanded cytotoxic T cell clones. Immunity 2022, 55: 1013-1031.e7. PMID: 35320704, PMCID: PMC9203927, DOI: 10.1016/j.immuni.2022.03.004.
- Filgotinib suppresses HIV-1-driven gene transcription by inhibiting HIV-1 splicing and T cell activationYeh YJ, Jenike KM, Calvi RM, Chiarella J, Hoh R, Deeks SG, Ho YC. Filgotinib suppresses HIV-1-driven gene transcription by inhibiting HIV-1 splicing and T cell activation. Journal Of Clinical Investigation 2020, 130: 4969-4984. PMID: 32573496, PMCID: PMC7456222, DOI: 10.1172/jci137371.
- Interferon opens up: HIV-induced inflammation reconfigures 3D chromatin conformation and affects where HIV integratesWei Y, Ho Y. Interferon opens up: HIV-induced inflammation reconfigures 3D chromatin conformation and affects where HIV integrates. Molecular Cell 2022, 82: 4585-4587. PMID: 36525953, PMCID: PMC9925257, DOI: 10.1016/j.molcel.2022.11.013.
- The loud minority: Transcriptionally active HIV-1-infected cells survive, proliferate, and persistCollora JA, Ho YC. The loud minority: Transcriptionally active HIV-1-infected cells survive, proliferate, and persist. Cell 2022, 185: 227-229. PMID: 35063069, PMCID: PMC9195179, DOI: 10.1016/j.cell.2021.12.038.
- A multidimensional HIV-1 persistence model for clonal expansion and viral rebound in vitroEshetu A, Ho YC. A multidimensional HIV-1 persistence model for clonal expansion and viral rebound in vitro. Cell Reports Methods 2021, 1: 100134. PMID: 35475216, PMCID: PMC9017154, DOI: 10.1016/j.crmeth.2021.100134.
- The Clonal Expansion Dynamics of the HIV-1 Reservoir: Mechanisms of Integration Site-Dependent Proliferation and HIV-1 PersistenceYeh YJ, Yang K, Razmi A, Ho YC. The Clonal Expansion Dynamics of the HIV-1 Reservoir: Mechanisms of Integration Site-Dependent Proliferation and HIV-1 Persistence. Viruses 2021, 13: 1858. PMID: 34578439, PMCID: PMC8473165, DOI: 10.3390/v13091858.
- Restriction of SARS-CoV-2 replication by targeting programmed −1 ribosomal frameshiftingSun Y, Abriola L, Niederer RO, Pedersen SF, Alfajaro MM, Silva Monteiro V, Wilen CB, Ho YC, Gilbert WV, Surovtseva YV, Lindenbach BD, Guo JU. Restriction of SARS-CoV-2 replication by targeting programmed −1 ribosomal frameshifting. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2023051118. PMID: 34185680, PMCID: PMC8256030, DOI: 10.1073/pnas.2023051118.
- Measuring the size and decay dynamics of the HIV-1 latent reservoirLiu R, Catalano AA, Ho YC. Measuring the size and decay dynamics of the HIV-1 latent reservoir. Cell Reports Medicine 2021, 2: 100249. PMID: 33948579, PMCID: PMC8080242, DOI: 10.1016/j.xcrm.2021.100249.
- Shock-and-kill versus block-and-lock: Targeting the fluctuating and heterogeneous HIV-1 gene expressionYeh YJ, Ho YC. Shock-and-kill versus block-and-lock: Targeting the fluctuating and heterogeneous HIV-1 gene expression. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2103692118. PMID: 33758027, PMCID: PMC8072369, DOI: 10.1073/pnas.2103692118.
- The XPB Subunit of the TFIIH Complex Plays a Critical Role in HIV-1 Transcription and XPB Inhibition by Spironolactone Prevents HIV-1 Reactivation from Latency.Mori L, Jenike K, Yeh YJ, Lacombe B, Li C, Getzler A, Mediouni S, Cameron M, Pipkin M, Ho YC, Ramirez BC, Valente S. The XPB Subunit of the TFIIH Complex Plays a Critical Role in HIV-1 Transcription and XPB Inhibition by Spironolactone Prevents HIV-1 Reactivation from Latency. Journal Of Virology 2020, 95 PMID: 33239456, PMCID: PMC7851559, DOI: 10.1128/jvi.01247-20.
- The single-cell landscape of immunological responses of CD4+ T cells in HIV versus severe acute respiratory syndrome coronavirus 2.Collora JA, Liu R, Albrecht K, Ho YC. The single-cell landscape of immunological responses of CD4+ T cells in HIV versus severe acute respiratory syndrome coronavirus 2. Current Opinion In HIV And AIDS 2020, 16: 36-47. PMID: 33165008, PMCID: PMC8162470, DOI: 10.1097/coh.0000000000000655.
- Recommendations for measuring HIV reservoir size in cure-directed clinical trialsAbdel-Mohsen M, Richman D, Siliciano RF, Nussenzweig MC, Howell BJ, Martinez-Picado J, Chomont N, Bar KJ, Yu XG, Lichterfeld M, Alcami J, Hazuda D, Bushman F, Siliciano JD, Betts MR, Spivak AM, Planelles V, Hahn BH, Smith DM, Ho YC, Buzon MJ, Gaebler C, Paiardini M, Li Q, Estes JD, Hope TJ, Kostman J, Mounzer K, Caskey M, Fox L, Frank I, Riley JL, Tebas P, Montaner LJ. Recommendations for measuring HIV reservoir size in cure-directed clinical trials. Nature Medicine 2020, 26: 1339-1350. PMID: 32895573, PMCID: PMC7703694, DOI: 10.1038/s41591-020-1022-1.
- Single-cell transcriptional landscapes reveal HIV-1–driven aberrant host gene transcription as a potential therapeutic targetLiu R, Yeh YJ, Varabyou A, Collora JA, Sherrill-Mix S, Talbot CC, Mehta S, Albrecht K, Hao H, Zhang H, Pollack RA, Beg SA, Calvi RM, Hu J, Durand CM, Ambinder RF, Hoh R, Deeks SG, Chiarella J, Spudich S, Douek DC, Bushman FD, Pertea M, Ho YC. Single-cell transcriptional landscapes reveal HIV-1–driven aberrant host gene transcription as a potential therapeutic target. Science Translational Medicine 2020, 12 PMID: 32404504, PMCID: PMC7453882, DOI: 10.1126/scitranslmed.aaz0802.
- SARS-CoV-2: A Storm is RagingPedersen SF, Ho YC. SARS-CoV-2: A Storm is Raging. Journal Of Clinical Investigation 2020, 130: 2202-2205. PMID: 32217834, PMCID: PMC7190904, DOI: 10.1172/jci137647.
- The forces driving clonal expansion of the HIV-1 latent reservoirLiu R, Simonetti FR, Ho YC. The forces driving clonal expansion of the HIV-1 latent reservoir. Virology Journal 2020, 17: 4. PMID: 31910871, PMCID: PMC6947923, DOI: 10.1186/s12985-019-1276-8.
- Defective HIV-1 Proviruses Are Expressed and Can Be Recognized by Cytotoxic T Lymphocytes, which Shape the Proviral LandscapePollack RA, Jones RB, Pertea M, Bruner KM, Martin AR, Thomas AS, Capoferri AA, Beg SA, Huang SH, Karandish S, Hao H, Halper-Stromberg E, Yong PC, Kovacs C, Benko E, Siliciano RF, Ho YC. Defective HIV-1 Proviruses Are Expressed and Can Be Recognized by Cytotoxic T Lymphocytes, which Shape the Proviral Landscape. Cell Host & Microbe 2017, 21: 494-506.e4. PMID: 28407485, PMCID: PMC5433942, DOI: 10.1016/j.chom.2017.03.008.
- Replication-Competent Noninduced Proviruses in the Latent Reservoir Increase Barrier to HIV-1 CureHo YC, Shan L, Hosmane NN, Wang J, Laskey SB, Rosenbloom DI, Lai J, Blankson JN, Siliciano JD, Siliciano RF. Replication-Competent Noninduced Proviruses in the Latent Reservoir Increase Barrier to HIV-1 Cure. Cell 2013, 155: 540-551. PMID: 24243014, PMCID: PMC3896327, DOI: 10.1016/j.cell.2013.09.020.
- Disseminated Cryptococcus neoformans var. grubii infections in intensive care unitsCHUANG Y, KU SC, LIAW SJ, WU SC, HO YC, YU CJ, HSUEH PR. Disseminated Cryptococcus neoformans var. grubii infections in intensive care units. Epidemiology And Infection 2009, 138: 1036-1043. PMID: 19796452, DOI: 10.1017/s0950268809990926.
- High Levels of mecA DNA Detected by a Quantitative Real-Time PCR Assay Are Associated with Mortality in Patients with Methicillin-Resistant Staphylococcus aureus BacteremiaHo Y, Chang S, Lin S, Wang W. High Levels of mecA DNA Detected by a Quantitative Real-Time PCR Assay Are Associated with Mortality in Patients with Methicillin-Resistant Staphylococcus aureus Bacteremia. Journal Of Clinical Microbiology 2009, 47: 2361-2361. PMCID: PMC2708482, DOI: 10.1128/jcm.00884-09.
- Disseminated cryptococcosis in HIV-uninfected patientsChuang Y, Ho Y, Chang H, Yu C, Yang P, Hsueh P. Disseminated cryptococcosis in HIV-uninfected patients. European Journal Of Clinical Microbiology & Infectious Diseases 2007, 27: 307-310. PMID: 18157678, DOI: 10.1007/s10096-007-0430-1.
- Isolation and Characterization of a Vibrio vulnificus Mutant Deficient in Both Extracellular Metalloprotease and CytolysinFan J, Shao C, Ho Y, Yu C, Hor L. Isolation and Characterization of a Vibrio vulnificus Mutant Deficient in Both Extracellular Metalloprotease and Cytolysin. Infection And Immunity 2001, 69: 5943-5948. PMID: 11500479, PMCID: PMC98719, DOI: 10.1128/iai.69.9.5943-5948.2001.
Clinical Trials
| Conditions | Study Title |
|---|---|
| COVID-19 Inpatient; COVID-19 Outpatient; Diseases of the Nervous System; HIV/AIDS; Infectious Diseases | HIV Associated Reservoirs and Comorbidities (The HARC Plus Study) |
| HIV/AIDS | Mechanisms of HIV latency |