Henrich Research

Stem Cell Transplantation and Gene Therapies for HIV Cure

We lead a study of HIV-1 persistence in the setting of cytoreductive chemotherapy and stem cell transplantation for concomitant malignancies. We have observed a sustained loss of detectable HIV-1 in peripheral blood and decreasing HIV-1 specific antibody levels following allogeneic HSCT with HIV-susceptible, wild-type CCR5 donor cells in patients on antiretroviral therapy. The virus eventually rebounded after ART interruption but led to prolonged ART-free remission prior to HIV-1 recrudescence. These experiments demonstrate that reservoir reduction alone is unlikely to lead to HIV-1 cure and that only one cell, or a small number of cells across the whole body, are likely responsible for viral rebound. Most recently, we have been collaborating with researchers at UC Davis to determine the impact on HIV reservoirs following autologous stem cell transplantation using gene modified cells resistant to HIV infection. This technology uses lentiviral vectors to transduce autologous stem cells and express genes that downregulate CCR5 expression, enhance intrinsic viral restriction and impair HIV-1 transcriptional reactivation. In addition, the Henrich Lab has implemented a novel, multiplexed single-cell-in-droplet assay to simultaneously identify and characterize gene-modified/HIV-infected cells using our novel scdPCR-based system to determine if gene-modified cells become infected with HIV-1 in vivo on ART and using analytical ART interruption (ATI).

Novel Virology Assay Development

Our laboratory is developing novel technologies to characterize viral reservoirs on the single-cell level. We are engaged in the development and validation of a novel single-cell assay using microfluidic methods and PCR for high-throughput viral characterization.  Our latest endeavor involves the development of point-of-care viral load assay development and utilizing non-viral biomarkers as surrogates for viral burden.

Identifying Biomarkers of HIV-1 Infected Cells and Targeting Transcriptionally Active Reservoirs

One of our major research ventures involves the use of antibody-drug conjugates (ADCs) to combat HIV-1 persistence. More specifically, we are characterizing the role of HIV-1 reactivation and determining the potential for Brentuximab vedotin, a CD30 antibody-drug conjugate, to clear infected cells in vitro and in vivo. We are using CRISP-Cas9 and in vitro infection models of various HIV-1 infection and HIV-1 gene transfection models to understand novel mechanisms by which HIV-1 can upregulate CD30 and other members of the TNF superfamily within infected cells to facilitate HIV viral transcriptional activity and infected cell survival.

HIV-1 and SARS-CoV-2 Persistence and Virus-Host Responses in Tissues Across the Whole Body

As a natural extension of our work in HIV-1 and SARS-CoV-2 persistence, we are focusing heavily on tissue-virus interactions, resulting inflammation, and viral mechanisms that allow for ongoing persistence in a variety of cell types across multiple tissues in several unique tissue-based cohorts. With unparalleled access to tissue, we are studying the burden of HIV-1, SARS-CoV-2 and other viruses across the whole body using novel high-dimensional multi-omic spatial profiling (DSP; e.g., Xenium, GeoMX) to quantitate various genomic and subgenomic viral transcripts and related viral host response gene responses directly in situ.

Direct Antiviral and Immune-Based Therapeutics for HIV and SARS-CoV-2

This lab oversees or participates in several viral-mechanistic studies using various antiviral and immune-based therapies to reduce HIV-1 and SARS-CoV-2 persistence. These include mTOR inhibition, IL15 super-agonist therapy to purge SARS-CoV-2 from tissues in those with Long COVID, and the use of a novel protease inhibitor to reduce SARS-CoV-2 persistence, among others.

Tissue Human Virome Project

Many of the novel tissue-based virus virus-host response assays that we have developed can be re-tooled for the study of various viruses (e.g., HIV and SARS-CoV-2 as above), and, given our unparalleled access to human tissues from are collaborating cohorts in relationship to our technological capabilities, we are part of the NIH-funded Human Virome Program (HVP). The goals of this major program are to determine viral infection across the whole body using metagenomic sequencing, spatial profiling, and machine learning/AI algorithms to determine interactions between viral infections and tissue host responses with single-cell resolution across the whole body, and overall health.

Program in Infectious Disease Molecular Imaging / PET Imaging of HIV and SARS-CoV-2 Persistence and Associated Immune Response

Our research group has initiated several NIH, industry, and foundation-supported nuclear medicine imaging studies involving first-in-human PET-based imaging techniques to directly identify persistent HIV proteins/viral activity and measures of T cell activation and ART drug penetration. Working in collaboration with the Department of Radiology and Nuclear Medicine, we are the first group to initiate HIV-specific PET imaging in human participants and work together to make UCSF the world leader in in-vivo imaging of HIV and infectious diseases. These imaging modalities have the potential to provide much-needed whole-body insights into viral persistence and response to various antiviral or anti-inflammatory pathways.

Long COVID and Post-Acute Sequelae of SARS-CoV-2 Infection (LIINC Study)

In March 2020, we pivoted rapidly to start the UCSF longitudinal COVID LIINC study to examine the longer-term impact of convalescent COVID-19 on human health. Drawing on our extensive experience in studying viral pathogenesis, virology, and viral persistence within the UCSF SCOPE cohort, we adapted our existing research enterprise to study the longer-term impact of convalescent COVID-19 on human health. We have since grown the UCSF LIINC cohort to include over 1,200 participants, collected over 70,000 unique biological samples, and established numerous internal and external collaborations. As a co-PI of the LIINC study, Timothy Henrich oversees many pathobiology studies and has focused the laboratory’s efforts on understanding the tissue virology of SARS-CoV-2 in the convalescent phase and to identify novel host-viral interactions that may be driving Long COVID physiology. LIINC - Long-term Impact of Infection with Novel Coronavirus (liincstudy.org)

 

 

For more information about our recent and past studies, please refer to the following link: https://www.ncbi.nlm.nih.gov/pubmed/?term=henrich+tj

 

If you are interested in collaborating with our lab on a project, please email Tim at [email protected].