Selected Grantee Publications
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- 229 results found
- Nonhuman Primate Models
Antiretroviral Therapy Timing Impacts Latent Tuberculosis Infection Reactivation in a Tuberculosis/Simian Immunodeficiency Virus Coinfection Model
Sharan et al., Journal of Clinical Investigation. 2021.
https://pubmed.ncbi.nlm.nih.gov/34855621/
In the rhesus macaque model for Mycobacterium tuberculosis plus simian immunodeficiency virus (SIV) co-infection, chronic immune activation rather than depletion of CD4+ T cells correlates with reactivation of latent tuberculosis infection (LTBI). Researchers administered combined antiretroviral therapy (cART) at 2 weeks post-SIV co-infection to study whether restoration of CD4+ T cell immunity occurred more broadly, and whether this prevented LTBI compared to cART initiated at 4 weeks post-SIV. Earlier initiation of cART enhanced survival led to better control of viral replication and reduced immune activation in the periphery and lung vasculature, thereby reducing the rate of SIV-induced reactivation. Supported by ORIP (K01OD031898, P51OD011133, P51OD011132, S10OD028653) and NIAID.
Monoclonal Antibodies Protect Aged Rhesus Macaques From SARS-CoV-2-Induced Immune Activation and Neuroinflammation
Verma et al., Cell Reports. 2021.
https://www.sciencedirect.com/science/article/pii/S2211124721014157?via%3Dihub%C2%A0=
In aged diabetic female rhesus macaques, prophylactic administration of neutralizing monoclonal antibodies (mAbs) effectively limits SARS-CoV-2 replication in both the upper and lower respiratory tract, and decreases immune activation, including reducing interferon-induced chemokines and limiting effector CD4 T cell influx into the cerebrospinal fluid. These protective mechanisms took place in the areas of the body targeted by the virus and may prevent adverse inflammatory consequences of SARS-CoV-2 infection in high-risk populations. Supported by ORIP (P51OD011107), NIAID, and NIA.
Blastocyst Development After Fertilization with In Vitro Spermatids Derived From Nonhuman Primate Embryonic Stem Cells
Khampang et al., F & Science. 2021.
https://www.sciencedirect.com/science/article/pii/S2666335X21000665?via%3Dihub%C2%A0=
Rhesus macaque pluripotent stem cells were differentiated into spermatogenic germ cell linages and matured in vitro to form spermatids that were capable of fertilizing oocytes (female or germ cells involved in reproduction) by intracytoplasmic spermatid injection (i.e., the egg is fertilized outside the body and the sperm is injected through a needle into the egg). Successful in vitro preimplantation embryo development was observed in approximately 12% of zygotes. The data suggest potential mechanisms to address male infertility. Supported by ORIP (R21OD020182, R01OD028223, P51OD011092).
CD4+ T Cells Are Dispensable for Induction of Broad Heterologous HIV Neutralizing Antibodies in Rhesus Macaques
Sarkar et al., Frontiers in Immunology. 2021.
https://www.frontiersin.org/articles/10.3389/fimmu.2021.757811/full
Researchers investigated the humoral response in vaccinated rhesus macaques with CD4+ T cell depletion, using the VC10014 DNA protein co-immunization vaccine platform (with gp160 plasmids and gp140 trimeric proteins derived from an HIV-1 infected subject). Both CD4+-depleted and non-depleted animals developed comparable Tier 1 and 2 heterologous HIV-1 neutralizing plasma antibody titers. Thus, primates generate HIV neutralizing antibodies in the absence of robust CD4+ T cell help, which has important implications for vaccine development. Supported by ORIP (P51OD011092, P40OD028116, U42OD023038, U42OD010426), NIAID, and NIDCR.
Comparative Cellular Analysis of Motor Cortex in Human, Marmoset and Mouse
Bakken et al., Nature. 2021.
https://pubmed.ncbi.nlm.nih.gov/34616062/
Investigators used high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmosets, and mice, to characterize the cellular makeup of the primary motor cortex (M1), which exhibits similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. Despite the overall conservation, many species-dependent specializations are apparent. These results demonstrate the robust molecular foundations of cell-type diversity in M1 across mammals and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations. Supported by ORIP (P51OD010425), NIMH, NCATS, NINDS, and NIDA.
A Novel Non-Human Primate Model of Pelizaeus-Merzbacher Disease
Sherman et al., Neurobiology of Disease. 2021.
https://www.sciencedirect.com/science/article/pii/S096999612100214X
Pelizaeus-Merzbacher disease (PMD) in humans is a severe hypomyelinating disorder of the central nervous system (CNS) linked to mutations in the proteolipid protein-1 (PLP1) gene. Investigators report on three spontaneous cases of male neonatal rhesus macaques (RMs) with clinical symptoms of hypomyelinating disease. Genetic analysis revealed that the parents of these related RMs carried a rare, hemizygous missense variant in exon 5 of the PLP1 gene. These RMs represent the first reported NHP model of PMD, providing an opportunity for studies to promote myelination in pediatric hypomyelinating diseases, as other animal models for PMD do not fully mimic the human disorder. Supported by ORIP (R24OD021324, P51OD011092, and S10OD025002) and NINDS.
Prior Infection With SARS-CoV-2 WA1/2020 Partially Protects Rhesus Macaques Against Re-Infection With B.1.1.7 and B.1.351 Variants
Chandrashekar et al., Science Translational Medicine. 2021.
https://doi.org/10.1126/scitranslmed.abj2641
Using the rhesus macaque model, researchers addressed whether natural immunity induced by the original SARS-CoV-2 WA1/2020 strain protects against re-challenge with B.1.1.7 and B.1.351, known as the alpha and beta variants of concern, respectively. The investigators infected rhesus macaques with WA1/2020 and re-challenged them on day 35 with WA1/2020 or with the alpha or beta variants. Natural immunity to WA1/2020 led to robust protection against re-challenge with WA1/2020, partial protection against beta, and an intermediate degree of protection against alpha. These findings have important implications for vaccination and public health strategies in the context of emerging SARS-CoV-2 variants of concern. Supported by ORIP (P51OD011106) and NCI.
Improving Rigor and Reproducibility in Nonhuman Primate Research
Bliss-Moreau et al., American Journal of Primatology. 2021.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629848/
Investigators across interdisciplinary fields consider approaches to enhance rigor and producibility in nonhuman primate (NHP) research. Given their similarity to humans, NHPs are often the animal model of choice for translational/preclinical biomedical research. However, availability of NHPs is limited. Hence, increased rigor is required to maximize the information gained from NHP studies. The co-authors consider approaches, such as, normative protocols, preregistration, data sharing, and how more extensive training in biostatics can enhance rigorous research in NHPs across biomedical disciplines. Supported by ORIP (P51OD011107, P51OD011106, P51OD011132, P51OD010425, P51OD011104, P51OD011092, and P51OD011133).
A Large Repertoire of B Cell Lineages Targeting One Cluster of Epitopes in a Vaccinated Rhesus Macaque
Li et al., Vaccine. 2021.
https://www.sciencedirect.com/science/article/pii/S0264410X21010355?via%3Dihub=
A rhesus macaque that was serially immunized six times with the 8-mer epitope for human monoclonal antibody (mAb) 447-52D—specific to the V3 region of gp120 HIV-1—provided a rare opportunity to study the repertoire of antibodies produced upon vaccination against a particular antigenic site. From a blood sample taken 3 weeks after the last immunization, researchers produced 41 V3-specific recombinant mAbs by single B cell isolation and cloning. Sequence analysis revealed 21 B cell lineages (single and clonally related). The broad repertoire of Abs directed to a small antigenic site shows the targeting potency of a vaccine-elicited immune response in rhesus macaques. Supported by ORIP (P51OD011092, U42OD010246) and NIAID.
IL-21 Enhances Influenza Vaccine Responses in Aged Macaques with Suppressed SIV Infection
Kvistad et al., JCI Insight. 2021.
https://doi.org/10.1172/jci.insight.150888
Aging with HIV is associated with low-grade systemic inflammation, immune senescence, and impaired antibody (Ab) responses to such vaccines as influenza (flu). Researchers investigated the role of interleukin (IL)-21, a CD4 T follicular helper cell regulator, on flu vaccine Ab response in rhesus macaques in the context of age and controlled simian immunodeficiency virus (SIV) mac239 infection. They found that IL-21 enhanced flu vaccine-induced Ab responses in SIV+ (anti-retroviral therapy-suppressed) aged rhesus macaques, adjuvanting the flu vaccine by modulating lymph node germinal center activity. Thus, strategies to supplement IL-21 in aging might improve vaccine responses in people aging with HIV. Supported by ORIP (R24OD010947) and NIAID.