Selected Grantee Publications
Evaluating a New Class of AKT/mTOR Activators for HIV Latency-Reversing Activity Ex Vivo and In Vivo
Gramatica et al., Journal of Virology. 2021.
https://doi.org/10.1128/JVI.02393-20
Activation of latent HIV-1 expression could benefit many HIV cure strategies. Researchers evaluated two AKT/mTOR activators, SB-216763 and tideglusib, as a potential new class of LRAs. The drugs reactivated latent HIV-1 present in blood samples from aviremic individuals on antiretroviral therapy without causing T cell activation or impaired effector function of cytotoxic T lymphocytes or NK cells. When tested in vivo in monkeys, tideglusib showed unfavorable pharmacodynamic properties and did not reverse SIV latency. The discordance between the ex vivo and in vivo results underscores the importance of developing novel LRAs that allow systemic drug delivery to relevant anatomical compartments. Supported by ORIP (P51OD011092), NIAID, NIGMS, NIMH, and NCI.
Lung Expression of Human Angiotensin-Converting Enzyme 2 Sensitizes the Mouse to SARS-CoV-2 Infection
Han et al., American Journal of Respiratory Cell and Molecular Biology. 2021.
https://doi.org/10.1165/rcmb.2020-0354OC
A rapidly deployable mouse model that recapitulates a disease caused by a novel pathogen would be a valuable research tool during a pandemic. Researchers were able to produce C57BL/6J mice with lung expression of human angiotensin-converting enzyme 2 (hACE2), the receptor for SARS-CoV-2. They did so by oropharyngeal delivery of a recombinant human adenovirus type 5 expressing hACE2. The transduced mice were then infected with SARS-CoV-2. Thereafter, the mice developed interstitial pneumonia with perivascular inflammation, exhibited higher viral load in lungs compared to controls, and displayed a gene expression phenotype resembling the clinical response in lungs of humans with COVID-19. Supported by ORIP (P51OD011104, R21OD024931), NHLBI, and NIGMS.
Sequence Diversity Analyses of an Improved Rhesus Macaque Genome Enhance its Biomedical Utility
Warren et al., Science. 2020.
https://science.sciencemag.org/content/370/6523/eabc6617
Investigators sequenced and assembled an Indian-origin female rhesus macaque (RM) genome using a multiplatform genomics approach that included long-read sequencing, extensive manual curation, and experimental validation to generate a new comprehensive annotated reference genome. As a result, 99.7% of the gaps in the earlier draft genome are now closed, and more than 99% of the genes are represented. Whole-genome sequencing of 853 RMs of both sexes identified 85.7 million single-nucleotide variants and 10.5 million indel variants, including potentially damaging variants in genes associated with human autism and developmental delay. The improved assembly of segmental duplications, new lineage-specific genes and expanded gene families provide a framework for developing noninvasive NHP models for human disease, as well as studies of genetic variation and phenotypic consequences. Supported by ORIP (P51OD011106, P51OD011107, P51OD011132, P51OD011104, U42OD024282, U42OD010568, R24OD011173, R24OD021324, R24OD010962), NHGRI, NIMH, NHLBI, and NIGMS.