Selected Grantee Publications
Tract Pathogen-Mediated Inflammation Through Development of Multimodal Treatment Regimen and Its Impact on SIV Acquisition in Rhesus Macaques
Bochart et al., PLOS Pathogens. 2021.
https://doi.org/10.1371/journal.ppat.1009565
In addition to being premier HIV models, rhesus macaques are models for other infectious diseases and colitis, where background colon health and inflammation may confound results. Starting with the standard specific-pathogen-free (SPF) model, researchers established a gastrointestinal pathogen-free (GPF) colony via multimodal therapy (enrofloxacin, azithromycin, fenbendazole, and paromomycin) to eliminate common endemic pathogens (EPs). This treatment combined with continued pathogen exclusion eliminated common EPs, improved mucosal barriers, and reduced mucosal and systemic inflammation without microbiota disruption. GPF animals challenged with SIV intrarectally demonstrated a more controlled and consistent rate of SIV acquisition, suggesting the value of this model for HIV studies. Supported by ORIP (U42OD023038, P51OD011092), NCI, and NIAID.
Psychosocial Stress Alters the Immune Response and Results in Higher Viral Load During Acute SIV Infection in a Pigtailed Macaque Model of HIV
Guerrero-Martin et al., Journal of Infectious Diseases. 2021.
https://doi.org/10.1093/infdis/jiab252
Social distancing is an important countermeasure for a pandemic, but social isolation may also have adverse health outcomes in the context of infectious diseases, such as HIV. Researchers compared commonly measured parameters of HIV progression between singly and socially housed simian immunodeficiency virus (SIV)-infected pigtailed macaques. Throughout acute SIV infection, singly housed pigtailed macaques had a higher viral load in the plasma and cerebrospinal fluid and demonstrated greater CD4+ T cell declines and more CD4+ and CD8+ T cell activation compared to socially housed macaques. These findings suggest that psychosocial stress could augment the progression of HIV infection. Supported by ORIP (U42OD013117, P40OD013117, K01OD018244), NIAID, NINDS, and NIMH.
Postpubertal Spermatogonial Stem Cell Transplantation Restores Functional Sperm Production in Rhesus Monkeys Irradiated Before and After Puberty
Shetty et al., Andrology. 2021.
https://onlinelibrary.wiley.com/doi/10.1111/andr.13033
Cancer treatment of prepubertal patients impacts future fertility due to the abolition of spermatogonial stem cells (SSCs). Prepubertal rhesus monkeys (n=6) were unilaterally castrated, and the remaining testes irradiated twice to insure loss of SSCs; the animals were treated with a vehicle or GnRH antagonist for 8 weeks (n=3/treatment). The cryopreserved prepubertal testicular tissue was allergenically transplanted into the intact testes of the monkeys after puberty. Recovery of viable donor epididymal sperm was observed in half the monkeys. These results illustrate that sperm production can be restored in primates by transplantation of testicular cells from cryopreserved untreated prepubertal testes into seminiferous tubules of the remaining testes. Supported by ORIP (P51OD011092), NICHD, and NCI.
Modulation of MHC-E Transport by Viral Decoy Ligands Is Required for RhCMV/SIV Vaccine Efficacy
Verweij et al., Science. 2021.
https://doi.org/10.1126/science.abe9233
Rhesus cytomegalovirus (RhCMV) strain 68-1-vectored simian immunodeficiency virus (SIV) vaccines elicit strong CD8+ T cell responses that can clear SIV infections. Peptides targeted by these T cells are presented on major histocompatibility complex (MHC) II and MHC-E rather than MHC-Ia. Researchers showed that VL9 drives intracellular transport of MHC-E and recognition of RhCMV-infected targets by MHC-E-restricted CD8+ T cells. Specific-pathogen-free (SPF) rhesus macaques vaccinated with a mutant 68-1 RhCMV lacking VL9 showed no priming of MHC-E-restricted CD8+ T cells and no protection against SIV, suggesting that future effective CMV-based HIV vaccines will require MHC-E-restricted CD8+ T cell priming. Supported by ORIP (U42OD023038, P51OD011092), NIAID, and NCI.
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.
Functional Convergence of a Germline-Encoded Neutralizing Antibody Response in Rhesus Macaques Immunized with HCV Envelope Glycoproteins
Chen et al., Immunity. 2021.
https://doi.org/10.1016/j.immuni.2021.02.013
Immunoglobulin heavy chain variable gene IGHV1-69-encoded broadly neutralizing antibodies (bnAbs) targeting the hepatitis C virus (HCV) envelope glycoprotein (Env) E2 are important for protection against HCV infection in humans. An IGHV1-69 ortholog, VH1.36, is preferentially used for bnAbs isolated from rhesus macaques immunized against HCV Env. Researchers investigated the genetic, structural, and functional properties of VH1.36-encoded bnAbs generated by HCV Env vaccination of macaques and compared their findings to IGHV1-69-encoded bnAbs from HCV patients. The investigators found that macaque VH1.36- and human IGHV1-69-encoded bnAbs share many common features, which provides an excellent framework for rational HCV vaccine design and testing. Supported by ORIP (P51OD011133, U42OD010442), NIAID, NCI, and NIGMS.
The SARS-CoV-2 Receptor and Other Key Components of the Renin-Angiotensin-Aldosterone System Related to COVID-19 are Expressed in Enterocytes in Larval Zebrafish
Postlethwait et al., Biology Open. 2021.
https://bio.biologists.org/content/10/3/bio058172.article-info
Hypertension and respiratory inflammation are exacerbated by the Renin-Angiotensin-Aldosterone System (RAAS), which normally protects from dropping blood pressure via Angiotensin II (Ang II) produced by the enzyme Ace. The Ace paralog Ace2 degrades Ang II and serves as the SARS-CoV-2 receptor. To exploit zebrafish to understand the relationship of RAAS to COVID-19, the group conducted genomic and phylogenetic analyses. Results identified a type of enterocyte as the expression site of zebrafish orthologs of key RAAS components, including the SARS-CoV-2 co-receptor. Results identified vascular cell subtypes expressing Ang II receptors and identified cell types to exploit zebrafish as a model for understanding COVID-19 mechanisms. Supported by ORIP (R24OD026591, R01OD011116), NIGMS, NICHD.
Metabolomics Analysis of Follicular Fluid Coupled With Oocyte Aspiration Reveals Importance of Glucocorticoids in Primate Periovulatory Follicle Competency
Ravisankar et al., Scientific Reports. 2021.
https://www.nature.com/articles/s41598-021-85704-6
Assisted reproductive therapy in primates requires ovarian stimulation protocols, which result in multiple heterogeneous oocytes with variable capacity for fertilization, cleavage, and blastocyst formation. Recovered oocytes from rhesus macaque follicles (n=74 follicles) were fertilized in vitro and classified as failed to cleave, cleaved but arrested, or able to form blastocysts. Metabolomics analysis of the follicular fluid identified 60 metabolites that were different among embryo classifications; key was an increase in the intrafollicular ratio of cortisol to cortisone in the blastocyst group, which was associated with translocation of the glucocorticoid receptor, NR3C1. The data suggest a role for NR3C1 in the regulation of follicular processes, such as expansion of cumulus granulosa cells, via paracrine signaling. Supported by ORIP (P51OD011092) and NICHD.
Virus Control in Vaccinated Rhesus Macaques Is Associated with Neutralizing and Capturing Antibodies Against the SHIV Challenge Virus but Not with V1V2 Vaccine–Induced Anti-V2 Antibodies Alone
Hessell et al., Journal of Immunology. 2021.
https://doi.org/10.4049/jimmunol.2001010
In the RV144 human immunodeficiency virus (HIV) vaccine trial, the only immune response associated with reduced infection was a high level of antibodies (Abs) targeting the second variable (V2) loop of the HIV envelope protein (Env). The mechanism underlying this suggested contribution of V2 Abs to protection remains unknown. Researchers tested the role of vaccine-induced anti-V2 Abs in rhesus macaques. Three vaccines strategies were designed to induce only V1V2 Abs before simian-human immunodeficiency virus (SHIV) challenge. Vaccine-induced V2 Abs did not independently control SHIV infection. However, neutralizing and virus capture anti-Env Abs were found to correlate with SHIV control. Supported by ORIP (P51OD011092) and NIAID.
Persistence of Viral RNA in Lymph Nodes in ART-suppressed SIV/SHIV-Infected Rhesus Macaques
Cadena et al., Nature Communications. 2021.
https://doi.org/10.1038/s41467-021-21724-0
The long-lived viral reservoir is a key obstacle to curing HIV/AIDS, yet the features of that reservoir during antiretroviral therapy (ART) remain poorly understood. Researchers undertook a comprehensive analysis of the SIV/SHIV reservoir in multiple lymphoid and non-lymphoid tissues from SIV/SHIV-infected rhesus macaques suppressed with ART for one year. Their findings support a model in which the tissue viral reservoir is rapidly and broadly seeded early during acute infection. Viral RNA persists lymphoid tissues despite a long period of suppressive ART. Therefore, viral latency does not appear to be universally transcriptionally silent; the reservoir may include a spectrum of latency depths. Supported by ORIP (R01OD024917) and NIAID.