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Nature Immunology Jun 2024Current prophylactic human immunodeficiency virus 1 (HIV-1) vaccine research aims to elicit broadly neutralizing antibodies (bnAbs). Membrane-proximal external region...
Current prophylactic human immunodeficiency virus 1 (HIV-1) vaccine research aims to elicit broadly neutralizing antibodies (bnAbs). Membrane-proximal external region (MPER)-targeting bnAbs, such as 10E8, provide exceptionally broad neutralization, but some are autoreactive. Here, we generated humanized B cell antigen receptor knock-in mouse models to test whether a series of germline-targeting immunogens could drive MPER-specific precursors toward bnAbs. We found that recruitment of 10E8 precursors to germinal centers (GCs) required a minimum affinity for germline-targeting immunogens, but the GC residency of MPER precursors was brief due to displacement by higher-affinity endogenous B cell competitors. Higher-affinity germline-targeting immunogens extended the GC residency of MPER precursors, but robust long-term GC residency and maturation were only observed for MPER-HuGL18, an MPER precursor clonotype able to close the affinity gap with endogenous B cell competitors in the GC. Thus, germline-targeting immunogens could induce MPER-targeting antibodies, and B cell residency in the GC may be regulated by a precursor-competitor affinity gap.
Topics: Germinal Center; Animals; Mice; Humans; B-Lymphocytes; HIV-1; HIV Antibodies; Antibody Affinity; Antibodies, Neutralizing; HIV Infections; AIDS Vaccines; Receptors, Antigen, B-Cell; Gene Knock-In Techniques; Mice, Transgenic; Broadly Neutralizing Antibodies; Mice, Inbred C57BL
PubMed: 38816616
DOI: 10.1038/s41590-024-01844-7 -
Nature Immunology Jun 2024A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high...
A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens, protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features.
Topics: Animals; Humans; HIV Envelope Protein gp41; HIV Antibodies; Mice; AIDS Vaccines; Macaca mulatta; Antibodies, Neutralizing; HIV-1; HIV Infections; Vaccination; Broadly Neutralizing Antibodies; B-Lymphocytes; Nanoparticles; Female; Complementarity Determining Regions; Epitopes
PubMed: 38816615
DOI: 10.1038/s41590-024-01833-w -
The Lancet. HIV Jun 2024Allogeneic haematopoietic stem-cell transplantation (allo-HSCT) markedly reduces HIV reservoirs, but the mechanisms by which this occurs are only partly understood. In... (Observational Study)
Observational Study
Dynamics of virological and immunological markers of HIV persistence after allogeneic haematopoietic stem-cell transplantation in the IciStem cohort: a prospective observational cohort study.
BACKGROUND
Allogeneic haematopoietic stem-cell transplantation (allo-HSCT) markedly reduces HIV reservoirs, but the mechanisms by which this occurs are only partly understood. In this study, we aimed to describe the dynamics of virological and immunological markers of HIV persistence after allo-HSCT.
METHODS
In this prospective observational cohort study, we analysed the viral reservoir and serological dynamics in IciStem cohort participants with HIV who had undergone allo-HSCT and were receiving antiretroviral therapy, ten of whom had received cells from donors with the CCR5Δ32 mutation. Participants from Belgium, Canada, Germany, Italy, the Netherlands, Spain, Switzerland, and the UK were included in the cohort both prospectively and retrospectively between June 1, 2014 and April 30, 2019. In the first 6 months after allo-HSCT, participants had monthly assessments, with annual assessments thereafter, with the protocol tailored to accommodate for the individual health status of each participant. HIV reservoirs were measured in blood and tissues and HIV-specific antibodies were measured in plasma. We used the Wilcoxon signed-rank test to compare data collected before and after allo-HSCT in participants for whom longitudinal data were available. When the paired test was not possible, we used the Mann-Whitney U test. We developed a mathematical model to study the factors influencing HIV reservoir reduction in people with HIV after allo-HSCT.
FINDINGS
We included 30 people with HIV with haematological malignancies who received a transplant between Sept 1, 2009 and April 30, 2019 and were enrolled within the IciStem cohort and included in this analysis. HIV reservoirs in peripheral blood were reduced immediately after full donor chimerism was achieved, generally accompanied by undetectable HIV-DNA in bone marrow, ileum, lymph nodes, and cerebrospinal fluid, regardless of donor CCR5 genotype. HIV-specific antibody levels and functionality values declined more slowly than direct HIV reservoir values, decaying significantly only months after full donor chimerism. Mathematical modelling suggests that allogeneic immunity mediated by donor cells is the main viral reservoir depletion mechanism after massive reservoir reduction during conditioning chemotherapy before allo-HSCT (half-life of latently infected replication-competent cells decreased from 44 months to 1·5 months).
INTERPRETATION
Our work provides, for the first time, data on the effects of allo-HSCT in the context of HIV infection. Additionally, we raise the question of which marker can serve as the last reporter of the residual viraemia, postulating that the absence of T-cell immune responses might be a more reliable marker than antibody decline after allo-HSCT.
FUNDING
amfAR (American Foundation for AIDS Research; ARCHE Program), National Institutes of Health, National Institute of Allergy and Infectious Diseases, and Dutch Aidsfonds.
Topics: Humans; Hematopoietic Stem Cell Transplantation; HIV Infections; Male; Prospective Studies; Female; Adult; Middle Aged; HIV-1; Transplantation, Homologous; Biomarkers; Viral Load; HIV Antibodies
PubMed: 38816141
DOI: 10.1016/S2352-3018(24)00090-0 -
Journal of Leukocyte Biology May 2024Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory loss and cognitive impairment. β-amyloid (Aβ) is one of the typical pathological...
Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory loss and cognitive impairment. β-amyloid (Aβ) is one of the typical pathological features of AD, and its accumulation leads to neuronal death from oxidative stress. Here, we found that hederagenin (HG), a natural product, exhibits anti-tumor, anti-inflammatory, anti-depressant, anti-neurodegenerative biological activities. However, whether HG has anti-Aβ activity remains unclear. Based on the characteristics of HG, it is hypothesized that HG has biological activity against Aβ injury. Therefore, Aβ-injured SH-SY5Y cells were constructed, and the protective effect of HG against Aβ injury was further evaluated using C. elegans. The results showed that HG increased superoxide dismutase activity, effectively reduced Aβ-induced oxidative damage, and reduced apoptosis via the PI3 K/Akt signaling pathway. HG inhibited Aβ deposition and delayed senescence and paralysis in the C. elegans strain, CL4176. HG showed inhibitory effects on Aβ; therefore, more natural active products are expected to be applied in AD therapy.
PubMed: 38814954
DOI: 10.1093/jleuko/qiae124 -
AIDS (London, England) Jul 2024
Topics: Humans; HIV Infections; COVID-19 Vaccines; COVID-19; SARS-CoV-2; mRNA Vaccines; Vaccines, Synthetic; Antibodies, Viral
PubMed: 38814720
DOI: 10.1097/01.aids.0001010204.00856.15 -
Turkish Journal of Medical Sciences 2023To determine the knowledge about and acceptance level of monkeypox vaccine in men who have sex with men (MSM).
BACKGROUND/AIM
To determine the knowledge about and acceptance level of monkeypox vaccine in men who have sex with men (MSM).
MATERIALS AND METHODS
A 14-item questionnaire, developed by the European Centers for Disease Control (ECDC), was presented online to MSM, aged ≥18 years old, via smartphone applications (Grindr and Hornet), between June 30th and August 12th, 2022.
RESULTS
Of the 737 participants who completed the survey, 678 were born in Türkiye and 59 were migrants/visitors born in different countries. All of the participants were living in Türkiye. The median age was 31 (range 18-68) years. Overall, 21.9% were HIV-positive, 94.9% were using antiretroviral therapy (ART), 3.9% reported using preexposure prophylaxis (PrEP), 9.9% had been diagnosed with a sexually transmitted infection (STI) in the past 12 months, and 10.1% reported using chemicals during sexual intercourse in the past three months.Participants aged 45-54 were significantly more concerned about being treated differently due to monkeypox than those in the other age groups (p = 0.038). Compared to the participants who were HIV-negative, those who were HIV-positive were significantly more worried about acquiring monkeypox (34.1% were very worried and 43.6% were worried, p = 0.033), were more likely to definitely or probably get vaccinated if offered (67.6% and 80.6%, respectively, p = 0.002), and were more concerned about being exposed to different attitudes due to monkeypox (37.0% and 53.3%, respectively, p < 0.01). Among those using ART, 82.3% and 50.0% reported that they would definitely or probably get vaccinated if offered, respectively (p = 0.046). There were no significant differences between groups for the remaining parameters.
CONCLUSION
Despite the low level of knowledge about monkeypox, the majority of the participants reported that they believed in the vaccine's efficacy. Those who were HIV-positive were particularly more concerned about monkeypox and were more willing to protect themselves compared to those who were HIV-negative.
Topics: Humans; Male; Adult; Middle Aged; Homosexuality, Male; Health Knowledge, Attitudes, Practice; Young Adult; Aged; Surveys and Questionnaires; Adolescent; Patient Acceptance of Health Care; Mpox (monkeypox); Turkey; HIV Infections
PubMed: 38813016
DOI: 10.55730/1300-0144.5679 -
Scientific Reports May 2024In order to become bioactive, proteins must be translated and protected from aggregation during biosynthesis. The ribosome and molecular chaperones play a key role in...
In order to become bioactive, proteins must be translated and protected from aggregation during biosynthesis. The ribosome and molecular chaperones play a key role in this process. Ribosome-bound nascent chains (RNCs) of intrinsically disordered proteins and RNCs bearing a signal/arrest sequence are known to interact with ribosomal proteins. However, in the case of RNCs bearing foldable protein sequences, not much information is available on these interactions. Here, via a combination of chemical crosslinking and time-resolved fluorescence-anisotropy, we find that nascent chains of the foldable globin apoHmp interact with ribosomal protein L23 and have a freely-tumbling non-interacting N-terminal compact region comprising 63-94 residues. Longer RNCs (apoHmp) also interact with an additional yet unidentified ribosomal protein, as well as with chaperones. Surprisingly, the apparent strength of RNC/r-protein interactions does not depend on nascent-chain sequence. Overall, foldable nascent chains establish and expand interactions with selected ribosomal proteins and chaperones, as they get longer. These data are significant because they reveal the interplay between independent conformational sampling and nascent-protein interactions with the ribosomal surface.
Topics: Ribosomes; Ribosomal Proteins; Protein Folding; Protein Binding; Molecular Chaperones; Intrinsically Disordered Proteins; Protein Biosynthesis; Models, Molecular; Protein Conformation; Humans
PubMed: 38811604
DOI: 10.1038/s41598-024-61274-1 -
Science Advances May 2024Viruses, bacteria, and parasites frequently cause infections in the gastrointestinal tract, but traditional vaccination strategies typically elicit little or no mucosal...
Viruses, bacteria, and parasites frequently cause infections in the gastrointestinal tract, but traditional vaccination strategies typically elicit little or no mucosal antibody responses. Here, we report a strategy to effectively concentrate immunogens and adjuvants in gut-draining lymph nodes (LNs) to induce gut-associated mucosal immunity. We prepared nanoemulsions (NEs) based on biodegradable oils commonly used as vaccine adjuvants, which encapsulated a potent Toll-like receptor agonist and displayed antigen conjugated to their surface. Following intraperitoneal administration, these NEs accumulated in gut-draining mesenteric LNs, priming strong germinal center responses and promoting B cell class switching to immunoglobulin A (IgA). Optimized NEs elicited 10- to 1000-fold higher antigen-specific IgG and IgA titers in the serum and feces, respectively, compared to free antigen mixed with NE, and strong neutralizing antibody titers against severe acute respiratory syndrome coronavirus 2. Thus, robust gut humoral immunity can be elicited by exploiting the unique lymphatic collection pathways of the gut with a lymph-targeting vaccine formulation.
Topics: Animals; Immunity, Humoral; Mice; Gastrointestinal Tract; Lymphoid Tissue; Immunity, Mucosal; SARS-CoV-2; COVID-19; Antibodies, Viral; Lymph Nodes; Immunoglobulin A; COVID-19 Vaccines; Antibodies, Neutralizing; Female; B-Lymphocytes; Adjuvants, Vaccine; Mice, Inbred C57BL; Humans
PubMed: 38809992
DOI: 10.1126/sciadv.adn7786 -
Global Health, Science and Practice Jun 2024There is limited evidence on COVID-19 vaccination uptake among people living with HIV (PLHIV) and health care workers (HCWs), with the current evidence concentrated in...
BACKGROUND
There is limited evidence on COVID-19 vaccination uptake among people living with HIV (PLHIV) and health care workers (HCWs), with the current evidence concentrated in high-income countries. There is also limited documentation in the published literature regarding the feasibility and lessons from implementing targeted vaccination strategies to reach PLHIV and HCWs in low- and middle-income countries.
PROGRAM DEVELOPMENT, PILOTING, AND IMPLEMENTATION
We designed and implemented multifaceted strategies to scale up targeted COVID-19 vaccination among PLHIV and HCWs in 11 administrative regions on the mainland of Tanzania plus Zanzibar. An initial 6-week intensification strategy was implemented using a diverse partnership model comprising key stakeholders at the national- and subnational levels. A layered package of strategies included expanding the number of certified vaccinators, creating vaccination points within HIV clinics, engaging HCWs to address their concerns, and building the capacity of HCWs as "champions" to promote and facilitate vaccination. We then closely monitored COVID-19 vaccination uptake in 562 high-volume HIV clinics. Between September 2021 and September 2022, the proportion of fully vaccinated adult PLHIV increased from <1% to 97% and fully vaccinated HCWs increased from 23% to 80%.
LESSONS AND IMPLICATIONS
Our intra-action review highlighted the importance of leveraging a strong foundation of existing partnerships and platforms, integrating COVID-19 vaccination points within HIV clinics, and refining strategies to increase vaccination demand while ensuring continuity of vaccine supply to meet the increased demand. Lessons from Tanzania can inform targeted vaccination of vulnerable groups in future health emergencies.
Topics: Humans; Tanzania; HIV Infections; Health Personnel; COVID-19; COVID-19 Vaccines; SARS-CoV-2; Vaccination
PubMed: 38806223
DOI: 10.9745/GHSP-D-23-00281 -
Nature Communications May 2024Avian influenza A virus H7N9 causes severe human infections with >30% fatality. Currently, there is no H7N9-specific prevention or treatment for humans. Here, from a...
Avian influenza A virus H7N9 causes severe human infections with >30% fatality. Currently, there is no H7N9-specific prevention or treatment for humans. Here, from a 2013 H7N9 convalescent case in Hong Kong, we isolate four hemagglutinin (HA)-reactive monoclonal antibodies (mAbs), with three directed to the globular head domain (HA1) and one to the stalk domain (HA2). Two clonally related HA1-directed mAbs, H7.HK1 and H7.HK2, potently neutralize H7N9 and protect female mice from lethal H7N9/AH1 challenge. Cryo-EM structures reveal that H7.HK1 and H7.HK2 bind to a β14-centered surface and disrupt the 220-loop that makes hydrophobic contacts with sialic acid on an adjacent protomer, thereby blocking viral entry. Sequence analysis indicates the lateral patch targeted by H7.HK1 and H7.HK2 to be conserved among influenza subtypes. Both H7.HK1 and H7.HK2 retain HA1 binding and neutralization capacity to later H7N9 isolates from 2016-2017, consistent with structural data showing that the antigenic mutations during this timeframe occur at their epitope peripheries. The HA2-directed mAb H7.HK4 lacks neutralizing activity but when used in combination with H7.HK2 moderately augments female mouse protection. Overall, our data reveal antibodies to a conserved lateral HA1 supersite that confer neutralization, and when combined with a HA2-directed non-neutralizing mAb, augment protection.
Topics: Influenza A Virus, H7N9 Subtype; Animals; Antibodies, Neutralizing; Humans; Hemagglutinin Glycoproteins, Influenza Virus; Female; Influenza, Human; Mice; Antibodies, Viral; Antibodies, Monoclonal; Mice, Inbred BALB C; Cryoelectron Microscopy; Orthomyxoviridae Infections; Epitopes
PubMed: 38802413
DOI: 10.1038/s41467-024-48758-4