Selected Grantee Publications
- Clear All
- 66 results found
- Vaccines/Therapeutics
- 2023
CD8+ Lymphocytes Do Not Impact SIV Reservoir Establishment under ART
Statzu et al., Nature Microbiology. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894752/
The HIV-1 latent reservoir has been shown to persist following antiretroviral therapy (ART), but the mechanisms underlying the establishment and maintenance of the reservoir are not fully understood. Using rhesus macaques of both sexes, investigators examined the effects of CD8+ T cells on formation of the latent reservoir with simian immunodeficiency virus (SIV) infection. They found that CD8+ T cell depletion resulted in slower decline of viremia but did not change the frequency of infected CD4+ T cells in the blood or lymph nodes. Additionally, the size of the persistent reservoir was unchanged. These findings suggest that the viral reservoir is established largely independent of SIV-specific cytotoxic T lymphocyte control. Supported by ORIP (P51OD011132), NIAID, NCI, NIDDK, NIDA, NHLBI, and NINDS.
Multimodal Single-Cell and Whole-Genome Sequencing of Small, Frozen Clinical Specimens
Wang et al., Nature Genetics. 2023.
https://www.nature.com/articles/s41588-022-01268-9
Single-cell RNA sequencing has led to improved understanding of tumor heterogeneity to drug response, but the broad application of those methods remains challenging due to practical requirements that are incompatible with clinical care workflow, such as the need for large and fresh tissues. The researchers demonstrated that several single-cell genomics techniques are feasible from small, frozen tissues and provide biological data outputs similar to those collected from fresh tissue while reducing artifactual signals and compositional biases introduced by fresh-tissue processing. These results provide a new perspective for translating these methods to clinical studies. Supported by ORIP (S10OD020056), NIAID, and NCI.
A Deep Learning Platform to Assess Drug Proarrhythmia Risk
Serrano et al., Cell Stem Cell. 2023.
https://www.sciencedirect.com/science/article/pii/S1934590922004866?via%3Dihub=
Investigators trained a convolutional neural network (CNN) classifier to learn and ultimately identify features of in vitro action potential recordings of human induced pluripotent stem cell (iPSC)–derived cardiomyocytes (hiPSC-CMs) that are associated with lethal Torsade de Pointes arrhythmia. The CNN classifier accurately predicted the risk of drug-induced arrhythmia. The risk profiles of the test drugs were similar across hiPSC-CMs derived from different healthy donors. In addition, pathogenic mutations that cause arrhythmogenic cardiomyopathies in patients significantly increased the proarrhythmic propensity to certain intermediate and high‑risk drugs in the hiPSC-CMs. These data indicate that deep learning can identify in vitro arrhythmic features that correlate with clinical arrhythmia and discern the influence of patient genetics on the risk of drug-induced arrhythmia. Supported by ORIP (S10OD030264) and NHLBI.
PGRN Deficiency Exacerbates, Whereas a Brain Penetrant PGRN Derivative Protects, GBA1 Mutation–Associated Pathologies and Diseases
Zhao et al., Proc Natl Acad Sci USA. 2023.
https://www.pnas.org/doi/10.1073/pnas.2210442120
Mutations in GBA1 are associated with Gaucher disease (GD) and are also genetic risks in developing Parkinson’s disease (PD). Investigators created a mouse model and demonstrated that progranulin (PGRN) deficiency in Gba1 mutant mice caused early onset and exacerbated GD phenotypes, leading to substantial increases in substrate accumulation and inflammation in visceral organs and the central nervous system. These in vivo and ex vivo data demonstrated that PGRN plays a crucial role in the initiation and progression. In addition, the mouse model provides a clinically relevant system for testing therapeutic approaches for GD and PD. Supported by ORIP (R21OD033660), NIAMS, and NINDS.
Surrogate Biomarkers of Disease Progression in Human Pegivirus Seropositive Human Immunodeficiency Virus–Infected Individuals
Vimali et al., Viral Immunology. 2023.
Researchers have previously observed that human pegivirus (HPgV) infection is associated with reduced progression of HIV. Investigators examined markers of HIV progression in male and female individuals with HIV and HPgV infection. They reported that HIV plasma viral load was lower in HPgV-seropositive individuals with HIV than in HPgV‑seronegative individuals with HIV. They also found that clinical markers of hepatic damage were significantly lower in HPgV-seropositive individuals with HIV. Future work could examine pathways through which HPgV influences HIV control, which might inform the development of new therapeutics. Supported by ORIP (P51OD011132) and NIAID.
Duration of Antiretroviral Therapy Impacts the Degree of Residual SIV Infection in the Gut in Long‐Term Non‐Progressing Chinese Rhesus Macaques
Solis-Leal et al., Journal of Medical Virology. 2023.
https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.28185
HIV and simian immunodeficiency virus (SIV) reservoirs have been shown to persist with antiretroviral therapy (ART), particularly in the gut‐associated lymphoid tissues in the intestine. The effects of ART on the reservoir size, however, had not been explored fully. In this study, researchers used male Chinese‐origin rhesus macaques to assess the effects of long- and short-term ART on gut infection—across segments of the small and large intestines—in long‐term non‐progressors (LTNPs). They reported that although ART does not eliminate SIV in LTNPs, a longer ART period dramatically reduces SIV infection and diversity in the gut. Further studies are needed to better understand the reduction of HIV gut reservoirs in this context. Supported by ORIP (P51OD011133, P51OD011104), NIAID, NIMH, and NINDS.