Selected Grantee Publications
Recrudescence of Natural Coccidioidomycosis During Combination Antiretroviral Therapy in a Pigtail Macaque Experimentally Infected with Simian Immunodeficiency Virus
Guerriero et al., AIDS Research and Human Retroviruses. 2021.
https://doi.org/10.1089/AID.2020.0228
Coccidioidomycosis is a common fungal infection in people living with HIV, particularly in regions where Coccidioides is endemic, such as the U.S. Southwest. Researchers diagnosed a recrudescent case of previously treated, naturally occurring coccidioidomycosis in a pigtail macaque experimentally infected with simian immunodeficiency virus (SIV) and virally suppressed on combination antiretroviral therapy (cART). Coccidioides IgG antibody titer became detectable before discontinuation of cART, but symptomatic coccidioidomycosis developed after cART withdrawal. This animal was screened and treated in accordance with the guidelines for coccidioidomycosis prevention and treatment. The researchers conclude that macaques with coccidioidomycosis history should be excluded from HIV studies. Supported by ORIP (P51OD010425), NIAID, and NIMH.
Western-Style Diet Consumption Impairs Maternal Insulin Sensitivity and Glucose Metabolism During Pregnancy in a Japanese Macaque Model
Elsakr et al., Scientific Reports. 2021.
https://www.nature.com/articles/s41598-021-92464-w
Using a Japanese macaque model, investigators assessed the metabolic effects of obesity and a calorically dense, Western-style diet (WSD; 36.3% fat), either alone or together, on maternal glucose tolerance and insulin levels in dams during pregnancy (n = 95 females followed over multiple pregnancies [n = 273]). With prolonged WSD feeding, multiple diet switches, and/or increasing age and parity, WSD was associated with increasingly higher insulin levels during glucose tolerance testing, indicative of insulin resistance. The results suggest that prolonged or recurrent calorically dense WSD and/or increased parity, rather than obesity per se, drive excess insulin resistance and metabolic dysfunction. Supported by ORIP (P51OD011092), NIDDK and NIMH.
Evidence in Primates Supporting the Use of Chemogenetics for the Treatment of Human Refractory Neuropsychiatric Disorders
Roseboom et al., Molecular Therapy. 2021.
https://doi.org/10.1016/j.ymthe.2021.04.021
A rhesus macaque model for pathological anxiety was used to investigate the feasibility of decreasing anxiety using chemogenetics, known as DREADDs (designer receptors exclusively activated by designer drugs), to reduce amygdala neuronal activity. A low-dose clozapine administration strategy was developed to induce DREADD-mediated amygdala inhibition. Compared to controls, clozapine selectively decreased anxiety-related freezing behavior in the human intruder paradigm in the chemogentic monkeys, while coo vocalizations and locomotion were unaffected. These results are an important step in establishing chemogenetic strategies for patients with refractory neuropsychiatric disorders in which amygdala alterations are central to disease pathophysiology. Supported by ORIP (P51OD011106), NIMH, and NICHD.
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.
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.