Selected Grantee Publications
Infection Order Outweighs the Role of CD4+ T Cells in Tertiary Flavivirus Exposure
Marzan-Rivera et al., iScience. 2022.
https://www.doi.org/10.1016/j.isci.2022.104764
The link between CD4+ T and B cells in immune responses to Dengue virus (DENV) and Zika virus (ZIKV) and their roles in cross-protection during heterologous infection are poorly known. The authors used CD4+ lymphocyte depletions to dissect the impact of cellular immunity on humoral responses during tertiary flavivirus infection in male macaques. CD4+ depletion in DENV/ZIKV–primed animals, followed by DENV, resulted in dysregulated adaptive immune responses. They show a delay in DENV-specific antibody titers and binding and neutralization in the DENV/ZIKV–primed, CD4-depleted animals but not in ZIKV/DENV–primed, CD4-depleted animals. This study confirms the role of CD4+ cells in priming an early humoral response during sequential flavivirus infections and suggests that the order of exposure affects the outcome of a tertiary infection. Supported by ORIP (P40OD012217), NIAID, and NIGMS.
Allogeneic MHC‑Matched T‑Cell Receptor Α/Β‑Depleted Bone Marrow Transplants in SHIV‑Infected, ART‑Suppressed Mauritian Cynomolgus Macaques
Weinfurter et al., Scientific Reports. 2022.
https://www.doi.org/10.1038/s41598-022-16306-z
Allogeneic hematopoietic stem cell transplants are effective in reducing HIV reservoirs following antiretroviral therapy (ART). A better understanding of this mechanism could enable the development of safer and more efficacious HIV treatment regimens. In this study, the researchers used a Mauritian cynomolgus macaque model to study the effects of allogeneic major histocompatibility complex–matched α/β T cell–depleted bone marrow cell transplantation following infection with simian–human immunodeficiency virus (SHIV). The macaques began ART 6 to 16 weeks post-infection. In three of the four macaques, SHIV DNA was undetectable in blood but persisted in other tissues. These results suggest that extended ART likely is needed to eradicate the HIV reservoir following transplantation. In future studies, full donor engraftment should be balanced with suppression of graft-versus-host disease. Supported by ORIP (P51OD011106, R24OD021322), and NCI.
Effects of Ex Vivo Blood Anticoagulation and Preanalytical Processing Time on the Proteome Content of Platelets
Yunga et al., Journal of Thrombosis and Haemostasis. 2022.
https://www.doi.org/10.1111/jth.15694
The investigators studied how various blood anticoagulation options and processing times affect platelet function and protein content ex vivo. Using platelet proteome quantification and triple quadrupole mass spectrometry, they found that anticoagulant-specific effects on platelet proteomes included increased complement system and decreased α-granule proteins in platelets from EDTA-anticoagulated blood. Heparinized blood had higher levels of histone and neutrophil-associated proteins, as well as formation of platelet–neutrophil extracellular trap interactions in whole blood ex vivo. The study indicates that different anticoagulants and preanalytical processing times affect platelet function and platelet protein content ex vivo, suggesting more rigorous phenotyping strategies for platelet omics studies. Supported by ORIP (S10OD012246), NHLBI, NCI and NEI.
Myeloid Cell Tropism Enables MHC-E–Restricted CD8+ T Cell Priming and Vaccine Efficacy by the RhCMV/SIV Vaccine
Hansen et al., Science Immunology. 2022.
https://www.doi.org/10.1126/sciimmunol.abn9301
Simian immunodeficiency virus (SIV) vaccines based on strain 68-1 rhesus cytomegalovirus vectors have been shown to arrest viral replication early in primary infection. The specific characteristics underlying this effect are not understood fully. In this study, the researchers used host microRNA–mediated vector tropism restriction to demonstrate that the targeted responses are dependent on vector infection of distinct cell types in a rhesus macaque model. Only vectors programmed to elicit major histocompatibility complex E–restricted CD8+ T cell responses provided protection against SIV challenge. These findings could be applied in the development of other vaccines for cancers and infectious diseases. Supported by ORIP (P51OD011092), NCI, and NIAID.
A Cellular Trafficking Signal in the SIV Envelope Protein Cytoplasmic Domain Is Strongly Selected for in Pathogenic Infection
Lawrence et al., PLOS Pathogens. 2022.
https://www.doi.org/10.1371/journal.ppat.1010507
Envelope glycoproteins within the cytoplasmic domain of HIV and simian immunodeficiency virus (SIV) include a tyrosine-based motif that mediates endocytosis and polarized sorting in infected cells. Mutation of this tracking signal has been shown to lead to suppressed viral replication and failed systemic immune activation, but the mechanism has not been explored fully. Using rhesus and pigtail macaque models, the researchers demonstrated that molecular clones containing the mutations reconstitute signals for both endocytosis and polarized sorting. Their findings suggest strong selection pressure for these processes during pathogenic HIV and SIV infection. Supported by ORIP (P51OD011104), NCI, and NIAID.
Early Post-Vaccination Gene Signatures Correlate With the Magnitude and Function of Vaccine-Induced HIV Envelope–Specific Plasma Antibodies in Infant Rhesus Macaques
Vijayan et al., Frontiers in Immunology. 2022.
https://www.doi.org/10.3389/fimmu.2022.840976
An effective vaccine is needed to reduce HIV infections, particularly among younger people. The initiation of an HIV vaccine regimen in early life could allow the development of mature HIV‑specific antibody responses that protect against infection. The investigators compared the effects of two vaccine regimens in infant rhesus macaques (sex not specified). Both vaccines induced a rapid innate response, indicated by elevated inflammatory plasma cytokines and altered gene expression. By performing a network analysis, the investigators identified differentially expressed genes associated with B cell activation. These findings suggest that vaccine-induced immunity can be optimized by modulating specific antibody and T cell responses. Supported by ORIP (P51OD011107), NCI, NIAID, and NIDCR.
Obesity Alters Pathology and Treatment Response in Inflammatory Disease
Bapat et al., Nature. 2022.
https://www.doi.org/10.1038/s41586-022-04536-0
Obesity and metabolic disease have been shown to affect immunotherapeutic outcomes. By studying classical type 2 T helper cells (TH2) in lean and obese male mouse models for atopic dermatitis, investigators found that the biologic therapies protected lean mice but exacerbated disease in obese mice. RNA sequencing and genome analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in TH2 cells in obese mice when compared to lean mice, indicating that PPARγ is required to prevent aberrant non-TH2 inflammation. Understanding the effects of obesity on immunological disease could inform a potential precision medicine approach to target obesity-induced immune dysregulation. Supported by ORIP (S10OD023689), NIAID, NCI, NIDDK, and NIGMS.
Presence of Natural Killer B Cells in Simian Immunodeficiency Virus–Infected Colon That Have Properties and Functions Similar to Those of Natural Killer Cells and B Cells but Are a Distinct Cell Population
Cogswell et al., mSphere. 2022.
https://www.doi.org/10.1128/jvi.00235-22
HIV infection of the gut is associated with increased mucosal inflammation, and the role of natural killer B (NKB) cells in this process requires further investigation. In this study, the researchers used rhesus and cynomolgus macaque models to characterize the function and characteristics of NKB cells in response to simian immunodeficiency virus (SIV) infection. They reported that NKB cells can kill target cells, proliferate, and express several inflammatory cytokines. The properties of NKB cells could provide insight into the inflammation observed in the gut during SIV infection, and the individual contributions of each cytokine and receptor–ligand interaction could be explored in a future study. Supported by ORIP (P51OD011106), NIAID, and NIGMS.
Vaccine-Induced, High-Magnitude HIV Env-Specific Antibodies with Fc-Mediated Effector Functions Are Insufficient to Protect Infant Rhesus Macaques against Oral SHIV Infection
Curtis et al., mSphere. 2022.
https://www.doi.org/10.1128/msphere.00839-21
A tailored, effective HIV vaccine is needed to prevent mother-to-child viral transmission. In nonhuman primate models, infection with simian–human immunodeficiency virus (SHIV) can be prevented by administering broadly neutralizing HIV envelope (Env)–specific antibodies. Investigators tested the efficacy of an intramuscular vaccine regimen against SHIV infection in male and female infant rhesus macaques. The vaccine induced Env-specific antibodies in plasma, with antibody-dependent cellular cytotoxicity and phagocytic function. These antibodies, however, were insufficient for protection against infection. Future studies could focus on improving the breadth of antibody response and improving cell-mediated immunity. Supported by ORIP (P51OD011107), NCI, NIAID, and NIDCR.
Reduced Infant Rhesus Macaque Growth Rates Due to Environmental Enteric Dysfunction and Association with Histopathology in the Large Intestine
Hendrickson et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-021-27925-x
Researchers characterized environmental enteric (relating to the intestines) dysfunction (EED) among infant rhesus macaques (n=80, both sexes) naturally exposed to enteric pathogens commonly linked to human growth stunting. Despite atrophy and abnormalities observed in the small intestine, poor growth trajectories and low serum tryptophan (an amino acid needed for protein and enzymes) levels were correlated with increased histopathology (microscopic tissue examination for disease manifestation) in the large intestine. This study provides insight into the mechanisms underlying EED and indicates that the large intestine may be an important target for therapeutic intervention. Supported by ORIP (P51OD011092, P51OD011107) and NIGMS.