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- Immunology
Cytomegalovirus Infection Facilitates the Costimulation of CD57+CD28- CD8 T Cells in HIV Infection and Atherosclerosis via the CD2–LFA-3 Axis
Winchester et al., Journal of Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38047900/
People with HIV are at increased risk of developing atherosclerosis and other cardiovascular diseases, and HIV coinfection with cytomegalovirus (CMV) is associated with immune activation and inflammation. In this study, researchers explored the role of the CD2–LFA-3 axis in driving activation and proliferation of CD57+CD28- CD8 T cells using clinical samples from patients with or without HIV. They propose a model in which CMV infection is linked to enhanced CD2 expression on the T cells, enabling the activation via LFA-3 signals and potentially leading to cardiopathogenic interactions with vascular endothelial cells that express LFA-3. This work provides a potential therapeutic target in atherosclerosis development and progression, especially for people with HIV. Supported by ORIP (P51OD011132, U24OD011023) and NIAID.
Antibiotic-Induced Gut Dysbiosis Elicits Gut–Brain–Axis Relevant Multi-Omic Signatures and Behavioral and Neuroendocrine Changes in a Nonhuman Primate Model
Hayer et al., Gut Microbes. 2024.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10826635/
Gut microbiome–mammalian cell interactions influence the development of metabolic, immune-mediated, and neuropsychiatric disorders. Dysbiosis of the gut microbiome has been linked to behavioral characteristics in previous nonhuman primate (NHP) studies, but additional studies using NHPs are necessary to understand microbiota–gut–brain communication. The authors sought to evaluate whether antibiotic-induced gut dysbiosis can elicit changes in gut metabolites and behavior indicative of gut–brain axis disruption in common marmosets of both sexes. For the first time in an NHP model, this study demonstrated that antibiotics induce gut dysbiosis, alter gut metabolites relevant to gut–brain communication, affect neuroendocrine responses in response to stressful stimuli, and change social behavior. Supported by ORIP (K01OD030514), NCI, and NIGMS.
Preclinical Safety and Biodistribution of CRISPR Targeting SIV in Non-Human Primates
Burdo et al., Gene Therapy. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11090835/
Nonhuman primates have served as a valuable resource for evaluating novel eradication and cure strategies for HIV infection. Using a male rhesus macaque model, researchers demonstrated the safety and utility of CRISPR gene-editing technology for targeting integrated simian immunodeficiency virus (SIV). Their work suggests that a single intravenous inoculation for HIV gene editing can be utilized to reach viral reservoirs throughout the body. Additionally, no off-target effects or abnormal pathology were observed. Together, these findings support the continued development of HIV eradicative cure strategies using CRISPR technology in humans. Supported by ORIP (P40OD012217, U42OD021458).
The Gene Expression Profile and Cell of Origin of Canine Peripheral T-Cell Lymphoma
Owens et al., BMC Cancer. 2024.
https://pubmed.ncbi.nlm.nih.gov/38166662/
Peripheral T-cell lymphoma (PTCL) refers to a heterogenous group of T-cell neoplasms with poor treatment responses and survival times. Canine PTCL clinically and immunophenotypically resembles the most common human subtype, PTCL-NOS (PTCL-not otherwise specified), and is a naturally occurring model for human PTCL. Gene expression profiling in human PTCL-NOS has helped characterize this ambiguous diagnosis into distinct subtypes, but similar gene expression profiling in canine PTCL is lacking. Canine CD4+ PTCL most closely resembles the GATA3-PTCL subtype of PTCL-NOS and may originate from an earlier stage of T-cell development than the more conventionally posited mature T-helper cell origin. Supported by ORIP (T32OD010437).
Newly Identified Roles for PIEZO1 Mechanosensor in Controlling Normal Megakaryocyte Development and in Primary Myelofibrosis
Abbonante et al., American Journal of Hematology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38165047/
Mechanisms through which mature megakaryocytes (Mks) and their progenitors sense the bone marrow extracellular matrix to promote lineage differentiation are only partially understood. The authors report that PIEZO1, a mechanosensitive cation channel, is expressed in mouse and human Mks, and activation of PIEZO1 increased the number of immature Mks in mice. Piezo1/2 knockout mice show an increase in Mk size and platelet count, both at basal state and upon marrow regeneration. Together, these data suggest that PIEZO1 places a brake on Mk maturation and platelet formation in physiology, and its upregulation might contribute to aggravating disease. Supported by ORIP (K01OD025290), NHGRI, NHLBI, and NCATS.
Stable HIV Decoy Receptor Expression After In Vivo HSC Transduction in Mice and NHPs: Safety and Efficacy in Protection From SHIV
Li, Molecular Therapy. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10124088/
Autologous hematopoietic stem cell (HSC) gene therapy offers a promising HIV treatment strategy, but cost, complexity, and toxicity remain significant challenges. Using female mice and female nonhuman primates (NHPs) (i.e., rhesus macaques), researchers developed an approach based on the stable expression of eCD4-Ig, a secreted decoy protein for HIV and simian–human immunodeficiency virus (SHIV) receptors. Their goals were to (1) assess the kinetics and serum level of eCD4-Ig, (2) evaluate the safety of HSC transduction with helper-dependent adenovirus–eCD4-Ig, and (3) test whether eCD4-Ig expression has a protective effect against viral challenge. They found that stable expression of the decoy receptor was achieved at therapeutically relevant levels. These data will guide future in vivo studies. Supported by ORIP (P51OD010425) and NHLBI.
Single-Component Multilayered Self-Assembling Protein Nanoparticles Presenting Glycan-Trimmed Uncleaved Prefusion Optimized Envelope Trimers as HIV-1 Vaccine Candidates
Zhang, Nature Communications. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10082823/
Researchers are interested in engineering protein nanoparticles to mimic virus-like particles for an HIV-1 vaccine. In this study, researchers explored a strategy that combines HIV envelope glycoprotein (Env) stabilization, nanoparticle display, and glycan trimming. They designed a panel of constructs for biochemical, biophysical, and structural characterization. Using female mice, female rabbits, and rhesus macaques of both sexes, they demonstrated that glycan trimming increases the frequency of vaccine responders and steers antibody responses away from immunodominant glycan holes and glycan patches. This work offers a potential strategy for overcoming the challenges posed by the Env glycan shield in vaccine development. Supported by ORIP (P51OD011133, P51OD011104, U42OD010442) and NIAID.
Vpr Attenuates Antiviral Immune Responses and Is Critical for Full Pathogenicity of SIVmac239 in Rhesus Macaques
Laliberté et al., iScience. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10679897/
The accessory viral protein R (Vpr) exhibits multilayered functions, and more work is needed to understand its roles in viral replication, immune evasion, and pathogenicity in vivo. Using male and female rhesus macaques, researchers examined how deletion of vpr affects simian immunodeficiency virus (SIV) replication kinetics, innate immune activation, B- and T-cell responses, and neutralizing activity. They found that lack of Vpr delays and attenuates viral replication during acute infection, allowing most animals to mount efficient and persisting immune responses and higher levels of neutralizing antibodies. Overall, these results suggest that Vpr promotes viral replication and innate immune evasion during acute SIV infection. Supported by ORIP (P51OD011133, P51OD011132, S10OD026799).
Deep Analysis of CD4 T Cells in the Rhesus CNS During SIV Infection
Elizaldi et al., PLOS Pathogens. 2023.
https://pubmed.ncbi.nlm.nih.gov/38060615/
Systemic HIV infection results in chronic inflammation that causes lasting damage to the central nervous system (CNS), despite long-term antiretroviral therapy (ART). Researchers studied neurocognitive outcomes in male and female rhesus macaques infected with simian immunodeficiency virus (SIV) using an ART regimen simulating suboptimal adherence; one group received no ART, and the other received ART with periodic interruptions. Using single-cell transcriptomic profiling, the researchers also identified molecular programs induced in the brain upon infection. They found that acute infection led to marked imbalance in the CNS CD4/CD8 T‑cell ratio, which persisted into the chronic phase. The studies provide insight into the role of CD4 T cells in the CNS during HIV infection. Supported by ORIP (P51OD011107, K01OD023034), NIA, NIAID, and NCI.
Cholera Toxin B Scaffolded, Focused SIV V2 Epitope Elicits Antibodies That Influence the Risk of SIVmac251 Acquisition in Macaques
Rahman et al., Frontiers in Immunology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37153584/
Previous work has indicated that the production of antibodies against epitopes in the V2 loop of gp120—a protein component of the viral spikes used to infiltrate host cells—correlates with protection from viral acquisition. Researchers assessed the efficacy of a simian immunodeficiency virus (SIV) vaccine consisting of a V2c epitope scaffolded onto cholera toxin B in rhesus macaques of both sexes. Immunized animals generated V2c-specific antibody responses, and differences in the functional antibody and immune cell responses were observed and compared with responses in a historically protective vaccine regimen. Different responses also were observed when varying adjuvants were administered with the vaccines. Thus, full protection against SIV infection might require vaccines against multiple spike epitopes. Supported by ORIP (P51OD011104, R24OD010976) and NIAID.