Selected Grantee Publications
CD8+ Cells and Small Viral Reservoirs Facilitate Post-ART Control of SIV Replication in M3+ Mauritian Cynomolgus Macaques Initiated on ART Two Weeks Post-Infection
Harwood et al., PLOS Pathogens. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10553806/
A rare group of people infected with HIV can achieve sustainable HIV remission after antiretroviral therapy (ART) withdrawal, but the underlying mechanisms are not understood fully. A team of investigators observed post-treatment control in a cohort of male cynomolgus macaques that were initiated on ART 2 weeks post-infection. Additionally, they reported that the cynomolgus macaques had smaller acute reservoirs than similarly infected rhesus macaques. Collectively, these data suggest that a combination of small reservoirs and immune-mediated virus suppression contributes to post-treatment control in cynomolgus macaques. This model could be used in future studies to develop therapeutic interventions. Supported by ORIP (P51OD011106, P40OD028116), NIAID, and NCI.
Host-Derived Growth Factors Drive ERK Phosphorylation and MCL1 Expression to Promote Osteosarcoma Cell Survival During Metastatic Lung Colonization
McAloney et al., Cellular Oncology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37676378/
Mortality from osteosarcoma is closely linked to lung metastasis, even though the lung appears to be a hostile environment for tumor cells. Using female mice, researchers assessed changes in both host and tumor cells during colonization. Their findings suggest that the mitogen-activated protein kinase (MAPK) pathway is significantly elevated in early and established metastases, which correlates with expression of anti-apoptotic genes (e.g., MCL1). The authors conclude that niche-derived growth factors drive increased MAPK activity and MCL1 expression in osteosarcoma, promoting metastatic colonization. This gene is a promising target for future therapeutic development. Supported by ORIP (K01OD031811), NCI, and NCATS.
The Latent Reservoir of Inducible, Infectious HIV-1 Does Not Decrease Despite Decades of Antiretroviral Therapy
McMyn et al., The Journal of Clinical Investigation. 2023.
https://www.doi.org/10.1172/JCI171554
Antiretroviral therapy (ART) does not eliminate the latent HIV reservoir, but it is unknown whether sustained reservoir decay occurs with long-term ART. Researchers used a quantitative viral outgrowth assay, an intact proviral DNA assay, and proviral sequencing to characterize the latent reservoir in men and women with HIV who had maintained suppression of viral replication on ART for 14 to 27 years. They found that the reservoir decay did not continue with long-term ART. Further studies could provide insight into the mechanism underlying these findings. These results reinforce the need for lifelong ART and indicate that the reservoir remains a major barrier to an HIV-1 cure. Supported by ORIP (R01OD011095), NIAID, and NIDCR.
Long-Acting Lenacapavir Protects Macaques Against Intravenous Challenge With Simian-Tropic HIV
Swanstrom et al., eBioMedicine. 2023.
https://doi.org/10.1016/j.ebiom.2023.104764
Pre-exposure prophylaxis (PrEP) is effective in preventing new HIV infections, but regimen adherence remains a challenge. Antiretrovirals with long-acting pharmacokinetic properties could help overcome this limitation. Researchers examined the protective efficacy of lenacapavir, a first-in-class HIV capsid inhibitor, using male pigtail macaques. They reported that a single administration of the drug provided protection from simian-tropic HIV infection. These data demonstrate the value of this nonhuman primate model and support the clinical development of long-acting lenacapavir for PrEP in humans. Future studies could further explore and refine the drug exposure–efficacy relationship. Supported by ORIP (P40OD028116), NIAID, and NCI.
A Novel Auxin-Inducible Degron System for Rapid, Cell Cycle–Specific Targeted Proteolysis
Capece et al., Cell Death and Differentiation. 2023.
https://www.nature.com/articles/s41418-023-01191-4
The discrimination of protein biological functions in different phases of the cell cycle is limited by the lack of experimental approaches that do not require pre-treatment with compounds affecting the cell-cycle progression. Therefore, potential cycle-specific biological functions of a protein of interest could be biased by the effects of cell treatments. The OsTIR1/auxin-inducible degron (AID) system allows “on-demand” selective and reversible protein degradation upon exposure to the phytohormone auxin. However, this technology does not allow researchers to study the effect of acute protein depletion selectively in one phase of the cell cycle, as auxin similarly affects all the treated cells irrespective of their proliferation status. Therefore, the AID system requires coupling with cell synchronization techniques, which can alter the basal biological status of the studied cell population, as with previously available approaches. Here, the investigators introduce the Regulate OsTIR1 Levels based on the Cell Cycle Status (ROLECCS) system, which induces proteolysis of both exogenously transfected and endogenous gene-edited targets in specific phases of the cell cycle. They propose the use of the ROLECCS system as a new and improved way of studying the differential roles that target proteins may have in specific phases of the cell cycle. Supported by ORIP (K01OD031811) and NCI.
Baseline Tumor Gene Expression Signatures Correlate With Chemoimmunotherapy Treatment Responsiveness in Canine B Cell Lymphoma
Dittrich et al., PLOS ONE. 2023.
https://pubmed.ncbi.nlm.nih.gov/37624862/
Pet dogs develop spontaneous diffuse large B cell lymphoma (DLBCL), and veterinary clinical trials have been employed to treat canine DLBCL and to inform clinical trials for their human companions. Investigators evaluated gene expression in lymph node aspirates from 18 trial dogs and defined good responders as those who relapsed after 90 days, and poor responders as those who relapsed prior to 90 days. They found increased CCND3 correlated with poor prognosis and increased CD36 correlated with good prognosis, as is observed in humans. These findings identify biomarkers that may help guide the choice of chemoimmunotherapy treatment in dogs. Supported by ORIP (K01OD028268) and NCI.
Intestinal Microbiota Controls Graft-Versus-Host Disease Independent of Donor–Host Genetic Disparity
Koyama et al., Immunity. 2023.
https://pubmed.ncbi.nlm.nih.gov/37480848/
Allogeneic hematopoietic stem cell transplantation is a curative therapy for hematopoietic malignancies and non-malignant diseases, but acute graft-versus-host disease (GVHD) remains a serious complication. Specifically, severe gut GVHD is the major cause of transplant-related mortality. Here, the authors show that genetically identical mice, sourced from different vendors, had distinct commensal bacterial compositions, which resulted in significantly discordant severity in GVHD. These studies highlight the importance of pre-transplant microbiota composition for the initiation and suppression of immune-mediated pathology in the gastrointestinal tract, demonstrating the impact of non-genetic environmental determinants to transplant outcome. Supported by ORIP (S10OD028685), NIA, NCI, and NHLBI.
Assessment of Various Standard Fish Diets on Gut Microbiome of Platyfish Xiphophorus maculatus
Soria et al., Journal of Experimental Zoology Part B. 2023.
https://onlinelibrary.wiley.com/doi/10.1002/jez.b.23218
Diet is an important factor affecting experimental reproducibility and data integration across studies. Reference diets for nontraditional animal models are needed to control diet-induced variation. In a study of the dietary impacts on the gut microbiome, researchers found that switching from a custom diet to a zebrafish diet altered the Xiphophorus gut microbiome. Their findings suggest that diets developed specifically for zebrafish can affect gut microbiome composition and might not be optimal for Xiphophorus. Supported by ORIP (R24OD011120, R24OD031467, P40OD011021) and NCI.
A Germ-Free Humanized Mouse Model Shows the Contribution of Resident Microbiota to Human-Specific Pathogen Infection
Wahl et al., Nature Biotechnology. 2023.
https://www.nature.com/articles/s41587-023-01906-5
Germ-free (GF) mice are of limited value in the study of human-specific pathogens because they do not support their replication. In this report, investigators developed a GF humanized mouse model using the bone marrow–liver–thymus platform to provide a robust and flexible in vivo model that can be used to study the role of resident microbiota in human health and disease. They demonstrated that resident microbiota promote viral acquisition and pathogenesis by using two human-specific pathogens, Epstein–Barr virus and HIV. Supported by ORIP (P40OD010995), FIC, NIAID, NCI, and NIDDK.
p38MAPKα Stromal Reprogramming Sensitizes Metastatic Breast Cancer to Immunotherapy
Faget et al., Cancer Discovery. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10238649/
This study emphasizes the importance of the metastatic tumor microenvironment in metastatic breast cancer growth and the identification of effective antimetastatic therapies. Using a stromal labeling approach and single-cell RNA sequencing, the authors showed that a combination of p38MAPK inhibition (p38i) and anti-OX40 synergistically reduced metastatic tumor growth and increased overall survival. Further engagement of cytotoxic T cells cured all metastatic disease in mice and produced durable immunologic memory. The Cancer Genome Atlas data analysis revealed that patients with p38i metastatic stromal signature and a high tumor mutational burden (TMB) had increased overall survival. These findings suggest that patients with high TMB would benefit the most from the p38i plus anti-OX40 approach. Supported by ORIP (S10OD028483), NIA, NCI, and NIGMS.