Selected Grantee Publications
A Participant-Derived Xenograft Model of HIV Enables Long-Term Evaluation of Autologous Immunotherapies
McCann et al., Journal of Experimental Medicine. 2021.
https://doi.org/10.1084/jem.20201908
HIV-specific CD8+ T cells partially control viral replication but rarely provide lasting protection due to immune escape. Investigators showed that engrafting NSG mice with memory CD4+ T cells from HIV+ donors enables evaluation of autologous T cell responses while avoiding graft-versus-host disease. Treating HIV-infected mice with clinically relevant T cell products reduced viremia. In vivo activity was significantly enhanced when T cells were engineered with surface-conjugated nanogels carrying an Interleukin-15 superagonist but was ultimately limited by the pervasive selection of escape mutations, recapitulating human patterns. This “participant-derived xenograft” model provides a powerful tool for developing T cell-based therapies for HIV. Supported by ORIP (R01OD011095), NIAID, NIDA, NIMH, NINDS, and NCATS.
A Chromosome-Level Genome of Astyanax mexicanus Surface Fish for Comparing Population-Specific Genetic Differences Contributing to Trait Evolution
Warren et al., Nature Communications. 2021.
https://pubmed.ncbi.nlm.nih.gov/33664263/
Identifying the genetic factors that underlie complex traits is central to understanding the mechanistic underpinnings of evolution. Cave-dwelling Astyanax mexicanus populations are well adapted to subterranean life and many populations appear to have evolved troglomorphic (morphological adaptation of an animal to living in the constant darkness of caves) traits independently, while the surface-dwelling populations can be used as a proxy for the ancestral form. Warren et al. present a high-resolution, chromosome-level surface fish genome, enabling the first genome-wide comparison between surface fish and cavefish populations. Using this resource, they performed quantitative trait locus (QTL) mapping analyses and found new candidate genes for eye loss (dusp26). They also generated the first genome-wide evaluation of deletion variability across cavefish populations to gain insight into this potential source of cave adaptation. The surface fish genome reference now provides a more complete resource for comparative, functional and genetic studies of drastic trait differences within a species. Supported by ORIP (R24OD011198), NIA, NICHD, NIGMS, amd NIDCR.
Trim-Away Mediated Knock Down Uncovers a New Function for Lbh During Gastrulation of Xenopus laevis
Weir et al., Developmental Biology. 2021.
https://pubmed.ncbi.nlm.nih.gov/33159936/
The protein Lbh was identified as necessary for cranial neural crest cell migration in Xenopus. To investigate its role in embryonic events, the authors employed the technique "Trim-Away" to degrade this maternally deposited protein. Trim-Away utilizes the E3 ubiquitin ligase trim21 to degrade proteins targeted with an antibody. Early knockdown of Lbh in Xenopus results in defects in gastrulation that present with a decrease in fibronectin matrix assembly, an increase in mesodermal cell migration and decrease in endodermal cell cohesion. The technique is also effective on a second abundant maternal Protein Kinase C And Casein Kinase Substrate In Neurons 2. Supported by ORIP (R24OD021485) and NIDCR.