Selected Grantee Publications
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- 357 results found
- Immunology
- Neurological
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.
Characterization of Near Full-Length Transmitted/Founder HIV-1 Subtype D and A/D Recombinant Genomes in a Heterosexual Ugandan Population (2006–2011)
Balinda et al., Viruses. 2022.
https://www.doi.org/10.3390/v14020334
About 80 percent of heterosexual HIV-1 transmission events are thought to be attributable to a single transmitted/founder (T/F) virus. Studies of HIV T/F viruses could yield valuable insights on transmission and help inform the design of vaccines and therapeutics. To date, most T/F studies have focused on subtype B and C viruses; few studies have focused on subtype D. In this study, the researchers characterized near full-length T/F viral genomes to identify subtype D and A/D recombinants from heterosexual mucosal transmissions in humans. They reported high viral diversity and high pathogenicity, underscoring the importance of matching vaccine designs to the predominant subtypes within populations. Further studies of the full genome sequence could provide additional information for subtyping. Supported by ORIP (P51OD011132) and NIAID.
Simian Immunodeficiency Virus Infection Mediated Changes in Jejunum and Peripheral SARS-CoV-2 Receptor ACE2 and Associated Proteins or Genes in Rhesus Macaques
Boby et al., Frontiers in Immunology. 2022.
https://www.doi.org/10.3389/fimmu.2022.835686
Recent studies suggest that people with HIV—particularly those not receiving antiretroviral therapy or those with low CD4 cell counts—are at increased risk of severe illness from SARS‑CoV-2 coinfection. Angiotensin-converting enzyme 2 (ACE2), the cellular receptor for SARS-CoV-2, is likely to play an important role in modulating physiological and pathological events during HIV infection. In this study, the researchers used a rhesus macaque model to characterize the expression profiles of ACE2, other renin-angiotensin system (RAS)–associated genes (AGTR1/2, ADAM17, and TMPRSS2), and inflammatory cytokines (IL-1β, IL-6, and TNF‑α) in the jejunum and lung during simian immunodeficiency virus (SIV) infection. SIV infection was associated with multiple changes in gene expression, including downregulation of ACE2, which could lead to loss of gut homeostasis. Further studies could provide insight on the role of RAS-associated proteins during HIV and SARS-CoV-2 co-infection. Supported by ORIP (P51OD011104) and NIDDK.
Functional and Ultrastructural Analysis of Reafferent Mechanosensation in Larval Zebrafish
Odstrcil et al., Current Biology. 2022.
https://www.sciencedirect.com/science/article/pii/S096098222101530X
All animals need to differentiate between exafferent stimuli (caused by the environment) and reafferent stimuli (caused by their own movement). Researchers characterized how hair cells in zebrafish larvae discriminate between reafferent and exafferent signals. Dye labeling of the lateral line nerve and functional imaging was combined with ultra-structural electron microscopy circuit reconstruction to show that cholinergic signals originating from the hindbrain transmit efference copies, and dopaminergic signals from the hypothalamus may affect threshold modulation. Findings suggest that this circuit is the core implementation of mechanosensory reafferent suppression in these young animals. Supported by ORIP (R43OD024879, R44OD024879) and NINDS.
Expression, Activity, and Regulation of Phosphorylating Enzymes in Tissues and Cells Relevant to HIV-1 Sexual Transmission
Hu et al., AIDS Research and Human Retroviruses. 2022.
https://www.doi.org/10.1089/AID.2020.0250
Phosphorylating enzymes (PEs) are critical for activating nucleoside/nucleotide reverse transcriptase inhibitors (e.g., tenofovir [TFV]), but limited information is available about the expression of PEs in the female genital tract and colon tissue. Investigators compared the mRNA expression of seven PEs involved in metabolism of TFV in cervicovaginal and colon tissues. This work involved human, pigtailed macaque, and rabbit tissues; human cervicovaginal epithelial cell lines; T cell lines; and primary CD4+ T cells. Taken together, this study suggests that TFV activation differs among immune cells and local tissues under varying conditions. Additionally, the variability of PE expression levels found across species provides critical information to assist with the interpretation of data obtained using these animal models. Supported by ORIP (P51OD010425) and NIAID.
Estimation of the In Vivo Neutralization Potency of eCD4Ig and Conditions for AAV-Mediated Production for SHIV Long-Term Remission
Goyal et al., Science Advances. 2022.
https://www.doi.org/10.1126/sciadv.abj5666
The engineered protein eCD4Ig, a synthetic antibody-like inhibitor designed to limit HIV entry into cells, shows promise as an approach to achieve HIV remission without antiretroviral therapy. Researchers used mathematical modeling to characterize in vivo antiviral neutralization of eCD4Ig, as well as possible antibody-dependent cell-mediated cytotoxicity effects, in rhesus macaques infected with simian–human immunodeficiency virus (SHIV) (sex not specified). The research team modeled SHIV and pharmacokinetics dynamics and projected the levels of eCD4Ig needed with a viral vector production approach to suppress SHIV viremia. The data suggest that endogenous, continuous expression of eCD4Ig could overcome the diminishing effects of antidrug antibodies and allow long-term remission of SHIV viremia in nonhuman primates. Supported by ORIP (P51OD011132) and NIAID.
Neuroinflammatory Profiling in SIV-Infected Chinese-Origin Rhesus Macaques on Antiretroviral Therapy
Solis-Leal et al., Viruses. 2022.
https://www.doi.org/10.3390/v14010139
The central nervous system (CNS) HIV reservoir contributes to residual neuroimmune activation, which can lead to HIV-associated neurocognitive disorder. Researchers characterized the expression of signaling molecules associated with inflammation in plasma, cerebrospinal fluid, and basal ganglia of Chinese-origin rhesus macaques (sex not specified) with simian immunodeficiency virus (SIV). They reported a correlation between levels of CCL2 in plasma and cerebrospinal fluid, suggesting that researchers could infer the degree of CNS inflammation by testing CCL2 levels in peripheral blood. Overall, these findings provide insight into neuroinflammation and signaling associated with HIV persistence in the CNS. Supported by ORIP (P51OD011104, P51OD011133), NIMH, and NINDS.
Protection from SARS-CoV-2 Delta One Year After mRNA-1273 Vaccination in Rhesus Macaques Coincides with Anamnestic Antibody Response in the Lung
Gagne et al., Cell. 2022.
https://www.sciencedirect.com/science/article/pii/S0092867421014057?via%3Dihub=
Efficacy of the vaccine mRNA-1273 against SARS-CoV-2 Delta decreases with time, yet there are limited data on how durability of immune responses affects protection. Researchers immunized male rhesus macaques with mRNA-1273 and challenged them with Delta one year later. Serum neutralizing antibody responses to Delta and protection in upper airway were low one year after mRNA-1273 vaccination. However, mRNA-1273 provided durable protection against Delta in the lower airway and against severe lung disease one year after vaccination, likely through anamnestic induction of antibody responses in the lung. These findings highlight the importance of booster shots for sustained upper and lower airway protection. Supported by ORIP (P51OD011132) and NIAID.
Immune Correlates Analysis of the mRNA-1273 COVID-19 Vaccine Efficacy Clinical Trial
Gilbert et al., Science. 2022.
https://pubmed.ncbi.nlm.nih.gov/34812653/
Investigators determined that antibodies are the correlate of protection in vaccinated individuals enrolled in the Moderna coronavirus efficacy phase 3 clinical trial. Vaccine recipients were assessed for neutralizing and binding antibodies as correlates of risk for COVID-19 disease and as correlates of protection. All markers were inversely associated with COVID-19 risk and directly associated with vaccine efficacy. These results help define immune marker correlates of protection and may guide approval decisions for messenger RNA (mRNA) COVID-19 vaccines and other COVID-19 vaccines. Supported by ORIP (S10OD028685).
Complement Blockade in Recipients Prevents Delayed Graft Function and Delays Antibody-mediated Rejection in a Nonhuman Primate Model of Kidney Transplantation
Eerhart et al., Transplantation. 2022.
Investigators evaluated the efficacy of a high-dose recombinant human C1 esterase inhibitor (rhC1INH) in preventing delayed graft function (DGF) in a rhesus macaque (RM) model for kidney transplantation after brain death and prolonged cold ischemia. The majority (4 of 5) of vehicle-treated recipients developed DGF, whereas DGF was observed in only 1 of 8 rhC1INH-treated recipients. RMs treated with rhC1INH also had faster creatine recovery, superior urinary output, and reduced biomarkers of allograft injury for the first week. The results suggest high-dose C1INH treatment in transplant recipients is an effective strategy to reduce kidney injury and inflammation, prevent DGF, delay antibody-mediated rejection development, and improve transplant outcomes. Supported by ORIP (P51OD011106), NIAID, and NIDDK.