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- Immunology
Potent HPIV3-Neutralizing IGHV5-51 Antibodies Identified from Multiple Individuals Show L Chain and CDRH3 Promiscuity
Abu-Shmais et al., Journal of Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38488511/
Human parainfluenza virus 3 fusion glycoprotein (HPIV3 F), responsible for facilitating viral entry into host cells, is a major target of neutralizing antibodies that inhibit infection. More work is needed to understand these dynamics. Researchers characterized the genetic signatures, epitope specificity, neutralization potential, and publicness of HPIV3-specific antibodies identified across multiple individuals. From this work, they identified 12 potently neutralizing antibodies targeting three nonoverlapping epitopes on HPIV3 F. Six of the antibodies used immunoglobulin heavy variable gene, IGHV 5-51. These antibodies used different L chain variable genes (VL) and diverse H chain CDR 3 (CDRH3) sequences. These findings help elucidate the genetic and functional characteristics of HPIV3-neutralizing antibodies and indicate the existence of a reproducible H chain variable–dependent antibody response associated with VL and CDRH3 promiscuity. Supported by ORIP (K01OD036063), NCATS, NCI, NEI, NIAID, and NIDDK.
Epigenetic MLH1 Silencing Concurs With Mismatch Repair Deficiency in Sporadic, Naturally Occurring Colorectal Cancer in Rhesus Macaques
Deycmar et al., Journal of Translational Medicine. 2024.
https://pubmed.ncbi.nlm.nih.gov/38504345
Rhesus macaques serve as a useful model for colorectal cancer (CRC) in humans, but more data are needed to understand the molecular pathogenesis of these cancers. Using male and female rhesus macaques, researchers investigated mismatch repair status, microsatellite instability, genetic mutations, transcriptional differences, and epigenetic alterations associated with CRC. Their data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. This work provides a uniquely informative model for human CRC. Supported by ORIP (P51OD011092, R24OD010947, R24OD021324, P40OD012217, U42OD010426, T35OD010946, T32OD010957), NCATS, and NCI.
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.
Exosome Cell Origin Affects In Vitro Markers of Tendon Repair in Ovine Macrophages and Tenocytes
von Stade et al., Tissue Engineering Part A. 2023.
https://pubmed.ncbi.nlm.nih.gov/36792933/
The underlying pathogenesis of rotator cuff tendinopathy reflects a combination of intrinsic and extrinsic factors, and recent work suggests that cell-to-cell communication drives the severity of tendon changes. Researchers are interested in the role of extracellular vesicles in tendon mechanical resilience, tissue organization, and anti-inflammatory macrophage phenotype predominance in response to tendon injury. In this study, investigators demonstrated how exosomes differ functionally based on cell source. This work suggests that control of exosome composition could lead to more effective therapies for certain tissues. Supported by ORIP (K01OD022982) and NCATS.
Sequential Intrahost Evolution and Onward Transmission of SARS-CoV-2 Variants
Gonzalez-Reiche et al., Nature Communications. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10239218/
Most patients with COVID-19 clear the virus upon resolution of acute infection, but a subset of immunocompromised individuals develop persistent SARS-CoV-2 infections. In this study, investigators describe sequential persistent SARS-CoV-2 infections in three individuals that led to the emergence, forward transmission, and continued evolution of the Omicron BA.1 variant Omicron BA.1.23. The study demonstrated that in the presence of suboptimal immune responses, persistent viral replication is an important driver of SARS-CoV-2 diversification. This and other studies also highlight that strategies to prevent virus persistence and shedding and more effective therapies are needed to limit the spread of newly emerging, neutralization-resistant variants in vulnerable patients. Supported by ORIP (S10OD026880, S10OD030463), NIAID, and NCATS.
Late Gene Expression–Deficient Cytomegalovirus Vectors Elicit Conventional T Cells That Do Not Protect Against SIV
Hansen et al., Journal of Clinical Investigation Insight. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10070102/
Cytomegalovirus (CMV)–based vaccines aim to exploit unique immunological adaptations, including host manipulation and immune evasion strategies. Translating CMV-based vaccines from rhesus macaques to humans requires translating the immune factors responsible for efficacy, as well as vaccine vectors that are sufficiently safe for widespread use. Researchers examined the impact of a stringent attenuation strategy on vector-induced immune protection against simian immunodeficiency virus (SIV) in rhesus macaques of both sexes. They reported that elicited CD8+ T cells exclusively failed to protect against SIV challenge. These data suggest that late viral gene expression and/or residual in vivo spreading are required to induce protective CD8+ T cell responses. Supported by ORIP (P51OD011092, P51OD011107, S10OD016261), NCI, NIAID, and NCATS.
Long-Term Evolutionary Adaptation of SIVcpz toward HIV-1 Using a Humanized Mouse Model
Schmitt et al., Journal of Medical Primatology. 2022.
https://www.doi.org/10.1111/jmp.12616
Chimpanzee-derived simian immunodeficiency viruses (SIVcpz) are thought to have evolved into the highly pathogenic HIV-1 Group M, but the genetic adaptations required for SIV progenitor viruses to become pathogenic and established as HIVs in the human population have remained unclear. Using humanized mice of both sexes, researchers mimicked the evolution of SIVcpz into HIV-1 Group M through serial passaging. After four generations, the researchers observed increased initial viral load, increased CD4+ T cell decline, and nonsynonymous substitutions. Overall, these data indicate increased viral fitness and pathogenicity. This work also demonstrates the utility of humanized mice in recreating the adaptive pressures necessary for the evolution of SIVcpz into HIV-1. Supported by ORIP (P51OD011104, P51OD011106), NCATS, and NIAID.
Reduced Alcohol Preference and Intake after Fecal Transplant in Patients with Alcohol Use Disorder Is Transmissible to Germ-Free Mice
Wolstenholme et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-34054-6
Alcohol use disorder is a major cause of reduced life expectancy worldwide, and this misuse has increased exponentially during the COVID-19 pandemic. Fecal microbiota transplant has been shown previously to reduce alcohol craving in humans with cirrhosis. Here, the investigators report that the reduction in craving and alcohol preference is transmissible to male germ-free mice only when live bacteria—and not germ-free supernatants—are used for colonization. This differential colonization was associated with alterations in the gut immune–inflammatory response through short-chain fatty acids. Supported by ORIP (P40OD010995), NIAAA, NIDDK, and NIMH.
Innate Immune Regulation in HIV Latency Models
Olson et al., Retrovirology. 2022.
https://www.doi.org/10.1186/s12977-022-00599-z
Researchers are interested in developing therapeutic approaches to target latent HIV reservoirs, which are unaffected by antiretroviral therapy. Previous studies suggest that HIV latency might be related to viral RNA sensing, interferon (IFN) signaling, and IFN-stimulated gene (ISG) activation. In this study, the researchers evaluated responses to stimulation by retinoic acid–inducible gene I agonists and IFN in multiple CD4+ T cell line models for HIV latency. The models represented various aspects of latent infection and viral control. Several of the cell lines demonstrated reduced ISG induction, suggesting that long-term latency might be related to dysregulation of the downstream IFN response. These effects likely reflect transcriptional changes occurring within a core set of ISGs and altering IFN responses. Additional studies could provide insight into the functions of these ISGs in HIV latency. Supported by ORIP (P51OD010425), NCATS, and NIAID.
Safety and Antiviral Activity of Triple Combination Broadly Neutralizing Monoclonal Antibody Therapy Against HIV-1: A Phase 1 Clinical Trial
Julg et al., Nature Medicine. 2022.
https://www.doi.org/10.1038/s41591-022-01815-1
Previous evidence suggests that at least three broadly neutralizing antibodies (bNAbs) targeting different epitope regions are needed for robust treatment and control of HIV. The investigators evaluated the safety, tolerability, and pharmacokinetics of PGDM1400, an HIV-1 V2-glycan–specific antibody, in a first-in-human trial. The primary endpoints were safety, tolerability, pharmacokinetics, and antiviral activity. The trial met the prespecified endpoints in male and female adults. These data will help advance understanding of the capabilities, limitations, and future role of bNAb combinations in HIV prevention and care. Supported by ORIP (R01OD024917), NIAID, and NCATS.