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- Immunology
Assessment of Anti-CD20 Antibody Pre-Treatment for Augmentation of CAR-T Cell Therapy in SIV-Infected Rhesus Macaques
Pampusch et al., Frontiers in Immunology. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9941136/
Chronic HIV replication occurs primarily within lymphoid follicles, and investigators hypothesized that temporary disruption of these follicles would create space for chimeric antigen receptor (CAR) T cell engraftment and lead to increased abundance and persistence of CAR T cells. They evaluated CAR T cell abundance and persistence in rhesus macaques of both sexes following simian immunodeficiency virus (SIV) infection and antiretroviral therapy suppression. Their results suggest that CAR T cells expanded to a greater extent in the depleted and CAR T cell–treated animals. Further studies are needed to evaluate strategies for engraftment and the persistence of HIV-specific CAR T cells. Supported by ORIP (P51OD011106, P51RR000167), NIAID, and NIDA.
SIV Infection Regulates Compartmentalization of Circulating Blood Plasma miRNAs within Extracellular Vesicles (EVs) and Extracellular Condensates (ECs) and Decreases EV-Associated miRNA-128
Kopcho et al., Viruses. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10059597/
MicroRNAs (miRNAs) are thought to be involved in HIV pathogenesis, but the effect of HIV on the compartmentalization of miRNAs within extracellular particles is unclear. Researchers sequenced the small RNA population of paired EVs and ECs from male rhesus macaques. They showed that extracellular miRNAs in blood plasma are not restricted to any type of extracellular particles but are associated with lipid‑based carriers, with a significant proportion associated with ECs. Further, simian immunodeficiency virus (SIV) infection altered the miRNAome profile of EVs and revealed miR‑128‑3p as a potential target of infection. This work suggests that EV‑ and EC‑associated miRNAs potentially could serve as biomarkers for various diseases. Supported by ORIP (P51OD011104, P51OD011133), NIAID, and NIDA.
Prolonged Experimental CD4+ T-Cell Depletion Does Not Cause Disease Progression In SIV-Infected African Green Monkeys
Le Hingrat et al., Nature Communications. 2023.
https://www.nature.com/articles/s41467-023-36379-2
Chronically simian immunodeficiency virus (SIV)–infected African green monkeys (AGMs) partially recover mucosal CD4+ T cells, maintain gut integrity, and do not progress to AIDS. Investigators assessed the impact of prolonged, antibody-mediated CD4+ T cell depletion on gut integrity and natural history of SIV infection in AGMs. All circulating CD4+ T cells and more than 90% of mucosal CD4+ T cells were depleted. Plasma viral loads and cell-associated viral RNA in tissues were lower in CD4+-cell-depleted animals. CD4+-cell-depleted AGMs maintained gut integrity, controlled immune activation, and did not progress to AIDS. Therefore, CD4+ T cell depletion is not a determinant of SIV-related gut dysfunction when gastrointestinal tract epithelial damage and inflammation are absent, suggesting that disease progression and resistance to AIDS are independent of CD4+ T cell restoration in SIV-infected AGMs. Supported by ORIP (P40OD028116), NIAID, NIDDK, and NHLBI.
CD8+ Lymphocytes Do Not Impact SIV Reservoir Establishment under ART
Statzu et al., Nature Microbiology. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894752/
The HIV-1 latent reservoir has been shown to persist following antiretroviral therapy (ART), but the mechanisms underlying the establishment and maintenance of the reservoir are not fully understood. Using rhesus macaques of both sexes, investigators examined the effects of CD8+ T cells on formation of the latent reservoir with simian immunodeficiency virus (SIV) infection. They found that CD8+ T cell depletion resulted in slower decline of viremia but did not change the frequency of infected CD4+ T cells in the blood or lymph nodes. Additionally, the size of the persistent reservoir was unchanged. These findings suggest that the viral reservoir is established largely independent of SIV-specific cytotoxic T lymphocyte control. Supported by ORIP (P51OD011132), NIAID, NCI, NIDDK, NIDA, NHLBI, and NINDS.
Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection
Abeynaike et al., Viruses. 2023.
https://www.mdpi.com/1999-4915/15/2/365
A major obstacle to human natural killer (NK) cell reconstitution is the lack of human interleukin‑15 (IL-15) signaling, as murine IL-15 is a poor stimulator of the human IL-15 receptor. Researchers show that immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice expressing a transgene encoding human IL-15 (NSG-Tg(IL-15)) have physiological levels of human IL-15 and support long-term engraftment of human NK cells when transplanted with human umbilical cord blood–derived hematopoietic stem cells (HSCs). These mice demonstrate robust and long-term reconstitution with human immune cells but do not develop graft-versus-host disease, allowing long-term studies of human NK cells. The HSC-engrafted mice can sustain HIV-1 infection, resulting in human NK cell responses. This work provides a robust novel model to study NK cell responses to HIV-1. Supported by ORIP (R24OD026440), NIAID, NCI, and NIDDK.
Elevated Transferrin Receptor Impairs T Cell Metabolism and Function in Systemic Lupus Erythematosus
Voss et al., Science Immunol. 2023.
https://www.science.org/doi/10.1126/sciimmunol.abq0178
Systemic lupus erythematosus (SLE) is an autoimmune disease in which dysfunctional T cells exhibit abnormalities in metabolism. Investigators performed a CRISPR screen to examine mechanisms associated with the role of excess iron in dysfunctional T cells. The transferrin receptor (CD71) was identified as differentially critical for Type 1 T helper cells and inhibitory for induced regulatory T cells. Activated T cells induced CD71 and iron uptake, which was exaggerated in SLE-prone T cells. Disease severity correlated with CD71 expression in cells from male and female patients with SLE, and blocking CD71 in vitro enhanced interleukin 10 secretion. These findings suggest that T cell iron uptake via CD71 contributes to T cell dysfunction and can be targeted to limit SLE-associated pathology. Supported by ORIP (S10OD030264), NIAID, NCI, and NIDDK.
The Ras GTPase‐Activating‐Like Protein IQGAP1 Bridges Gasdermin D to the ESCRT System to Promote IL‐1β Release via Exosomes
Liao et al., The EMBO Journal. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9811620/
The investigators identified IQGAP1, a scaffold protein, as a gasdermin D (GSDMD)–interacting protein through a nonbiased proteomic analysis. Functional investigation indicated that the interaction is required for lipopolysaccharide (LPS)- and ATP-induced exosome release. Further analysis revealed that IQGAP1 serves as an adaptor that bridges GSDMD and the associated IL‐1β complex to Tsg101 and enables the packaging of GSDMD and IL‐1β into exosomes. This process is dependent on an LPS‐induced increase in GTP‐bound CDC42, a small GTPase known to activate IQGAP1. This study reveals IQGAP1 as a link between inflammasome activation and exosomal release of IL‐1β. Supported by ORIP (S10OD023436) and NIAID.
Recombinant Simian Varicella Virus–Simian Immunodeficiency Virus Vaccine Induces T and B Cell Functions and Provides Partial Protection Against Repeated Mucosal SIV Challenges in Rhesus Macaques
Pahar et al., Viruses. 2022.
https://www.doi.org/10.3390/v14122819
An effective vaccine is needed urgently to control the global HIV epidemic completely by 2030. Recombinant simian varicella virus (rSVV) vaccines expressing SIV antigens offer a potential new approach in the evaluation of HIV vaccine candidates. Building on their previous findings, the investigators induced systemic and mucosal immune responses with live, attenuated rSVV vaccinations followed by SIV group–specific antigen and SIV envelope protein boosts in female rhesus macaques treated with repeated intravaginal SIV challenges. Their findings demonstrate that the vaccination with protein boosts induces a 37.5% efficacy rate against pathogenic SIV challenge by generating mucosal memory, virus‑specific neutralizing antibodies, binding antibodies, and polyfunctional T cell responses. Supported by ORIP (P51OD011104) and NIAID.
Gut Microbiome Dysbiosis in Antibiotic-Treated COVID-19 Patients Is Associated with Microbial Translocation and Bacteremia
Bernard-Raichon et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-33395-6
The investigators demonstrated that SARS-CoV-2 infection induced gut microbiome dysbiosis in male mice. Samples collected from human COVID-19 patients of both sexes also revealed substantial gut microbiome dysbiosis. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data indicated that bacteria might translocate from the gut into the systemic circulation of COVID-19 patients. These results were consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID-19. Supported by ORIP (S10OD021747), NCI, NHLBI, NIAID, and NIDDK.
Transient T Cell Expansion, Activation, and Proliferation in Therapeutically Vaccinated Simian Immunodeficiency Virus–Positive Macaques Treated with N-803
Harwood et al., Journal of Virology. 2022.
https://www.doi.org/10.1128/jvi.01424-22
Many HIV vaccine strategies induce neutralizing antibodies and CD8+ T cells, but more information on these protective immune responses is needed. Researchers hypothesized that CD8+ T cells elicited by vaccination during antiretroviral therapy (ART) would be recalled and boosted by treatment with N-803 after ART discontinuation. They tested this approach in male Mauritian cynomolgus macaques infected with simian immunodeficiency virus. The regimen enhanced the frequency of Gag-specific lymphocytes with phenotypes associated with activation, proliferation, and memory in the peripheral blood and lymph nodes of vaccinated animals. These results help demonstrate N-803’s potential as an immunomodulatory agent for treatment of HIV. Supported by ORIP (P51OD011106) and NIAID.