Selected Grantee Publications
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.
Generation of SIV-Resistant T Cells and Macrophages from Nonhuman Primate Induced Pluripotent Stem Cells with Edited CCR5 Locus
D’Souza et al., Stem Cell Reports. 2022.
https://www.doi.org/10.1016/j.stemcr.2022.03.003
Genetically modified T cells have shown promise as a potential therapy for HIV. A renewable source of T cells from induced pluripotent stem cells (iPSCs) could help to further research progress in this area. The researchers used Mauritian cynomolgus macaques to generate simian immunodeficiency virus (SIV)–resistant T cells and macrophages from iPSCs. These engineered cells demonstrated impaired capacity for differentiation into CD4+CD8+ T cells. T cells and macrophages from the edited iPSCs did not support SIV replication. These findings could be applied to the development of new HIV therapies. Supported by ORIP (R24OD021322, P51OD011106) and NHLBI.
A Potent Myeloid Response Is Rapidly Activated in the Lungs of Premature Rhesus Macaques Exposed to Intra-Uterine Inflammation
Jackson et al., Mucosal Immunology. 2022.
https://www.doi.org/10.1038/s41385-022-00495-x
Up to 40% of preterm births are associated with histological chorioamnionitis (HCA), which can lead to neonatal mortality, sepsis, respiratory disease, and neurodevelopmental problem. Researchers used rhesus macaques to comprehensively describe HCA-induced fetal mucosal immune responses and delineate the individual roles of IL-1β and TNFα in HCA-induced fetal pathology. Their data indicate that the fetal innate immune system can mount a rapid, multifaceted pulmonary immune response to in utero exposure to inflammation. Taken together, this work provides mechanistic insights into the association between HCA and the postnatal lung morbidities of the premature infant and highlights the therapeutic potential of inflammatory blockade in the fetus. Supported by ORIP (P51OD011107), NIEHS, NIDDK, NHLBI, and NICHD.
CAR/CXCR5–T Cell Immunotherapy Is Safe and Potentially Efficacious in Promoting Sustained Remission of SIV Infection
Pampusch et al., PLOS Pathogens. 2022.
https://www.doi.org/10.1371/journal.ppat.1009831
HIV and simian immunodeficiency virus (SIV) replication are concentrated within the B cell follicles of secondary lymphoid tissues. In this study, the researchers developed immunotherapeutic chimeric antigen receptor (CAR) T cells that home to follicles and clear SIV-infected cells in a rhesus macaque model. The CAR T cells localized to the follicle, replicated, and interacted directly with infected cells. Most of the treated animals maintained lower viral loads in the blood and follicles, compared to control animals. These findings demonstrate the safety and potential efficacy of this immunotherapy approach for long-term remission of HIV without requiring the lifelong use of antiretroviral therapy. Supported by ORIP (P51OD011106), NIAID, and NHLBI.
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.
The Immune Landscape in Tuberculosis Reveals Populations Linked to Disease and Latency
Esaulova et al., Cell Host Microbe. 2020.
https://pubmed.ncbi.nlm.nih.gov/33340449/
Mycobacterium tuberculosis infection of adult rhesus macaques (RMs), predominantly males (81%), recapitulates both latent (LTBI) and active pulmonary TB (PTB) observed in humans. The immune characterization in lungs of RMs with PTB exhibited an influx of plasmacytoid dendritic cells, an interferon-responsive macrophage population, and activated T cell responses. In contrast, a CD27+ natural killer (NK) cell subset accumulated in the lungs of RMs with LTBI. This NK cell population was also detected in the circulation of humans with LTBI. This characterization of lung immune cells enhances our understanding of TB immunopathogenesis and provides potential targets for therapies and vaccines for TB control. Supported by ORIP (P51OD011104 and P51OD011133), NHLBI, and NIAID.