A New Vaccine to Battle Covid-19 Haynes, Barton F
The New England journal of medicine,
02/2021, Volume:
384, Issue:
5
Journal Article
Peer reviewed
Open access
The United States and many parts of the world have now lost control of the Covid-19 pandemic owing to the respiratory spread of SARS-CoV-2 and to inconsistent adherence to effective public health ...measures, including wearing masks and maintaining social distancing. Persons infected with SARS-CoV-2 are frequently asymptomatic, yet they have high respiratory viral loads, and they are major purveyors of viral spread. These factors have led to the current explosion of Covid-19 hospitalizations and deaths, with Covid-19 now a major cause of death in the United States. Our only hope is safe and effective vaccines that can be widely deployed . . .
Summary
The development of an effective vaccine has been hindered by the enormous diversity of human immunodeficiency virus‐1 (HIV‐1) and its ability to escape a myriad of host immune responses. In ...addition, conserved vulnerable regions on the HIV‐1 envelope glycoprotein are often poorly immunogenic and elicit broadly neutralizing antibody responses (BNAbs) in a minority of HIV‐1‐infected individuals and only after several years of infection. All of the known BNAbs demonstrate high levels of somatic mutations and often display other unusual traits, such as a long heavy chain complementarity determining region 3 (CDRH3) and autoreactivity that can be limited by host tolerance controls. Nonetheless, the demonstration that HIV‐1‐infected individuals can make potent BNAbs is encouraging, and recent progress in isolating such antibodies and mapping their immune pathways of development is providing new strategies for vaccination.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Highlights • New progress has been made in understanding effective protective mechanisms of anti-HIV CD8 cytolytic T lymphocytes. • New progress has been made in understanding the mechanisms of ...induction of broadly reactive neutralizing antibodies. • New progress has been made in elucidation of the structure of the HIV envelope trimer. • New strategies have been developed for induction of protective T and B cell responses to HIV infection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
This Pillars of Immunology article is a commentary on “HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease,” a pivotal article written by G. ...Pantaleo, C. Graziosi, J. F. Demarest, L. Butini, M. Montroni, C. H. Fox, J. M. Orenstein, D. P. Kotler, and A. S. Fauci, and published in Nature, in 1993. https://www.nature.com/articles/362355a0. The Journal of Immunology, 2023, 210: 1181–1182
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with multiple spike mutations enable increased transmission and antibody resistance. We combined cryo-electron microscopy ...(cryo-EM), binding, and computational analyses to study variant spikes, including one that was involved in transmission between minks and humans, and others that originated and spread in human populations. All variants showed increased angiotensin-converting enzyme 2 (ACE2) receptor binding and increased propensity for receptor binding domain (RBD)-up states. While adaptation to mink resulted in spike destabilization, the B.1.1.7 (UK) spike balanced stabilizing and destabilizing mutations. A local destabilizing effect of the RBD E484K mutation was implicated in resistance of the B.1.1.28/P.1 (Brazil) and B.1.351 (South Africa) variants to neutralizing antibodies. Our studies revealed allosteric effects of mutations and mechanistic differences that drive either interspecies transmission or escape from antibody neutralization.
Summary
Induction of broadly neutralizing antibodies (bNAbs) is a major goal of HIV vaccine development. BNAbs are made during HIV infection by a subset of individuals but currently cannot be induced ...in the setting of vaccination. Considerable progress has been made recently in understanding host immunologic controls of bNAb induction and maturation in the setting of HIV infection, and point to key roles for both central and peripheral immunologic tolerance mechanisms in limiting bnAb development. Immune tolerance checkpoint inhibition has been transformative in promotion of anti‐tumor CD8 T‐cell responses in the treatment of certain malignancies. Here, we review the evidence for host controls of bNAb responses, and discuss strategies for the transient modulation of immune responses with vaccines toward the goal of enhancing germinal center B‐cell responses to favor bNAb B‐cell lineages and to foster their maturation to full neutralization potency.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein is the target of vaccine design efforts to end the coronavirus disease 2019 (COVID-19) pandemic. Despite a low mutation rate, ...isolates with the D614G substitution in the S protein appeared early during the pandemic and are now the dominant form worldwide. Here, we explore S conformational changes and the effects of the D614G mutation on a soluble S ectodomain construct. Cryoelectron microscopy (cryo-EM) structures reveal altered receptor binding domain (RBD) disposition; antigenicity and proteolysis experiments reveal structural changes and enhanced furin cleavage efficiency of the G614 variant. Furthermore, furin cleavage alters the up/down ratio of the RBDs in the G614 S ectodomain, demonstrating an allosteric effect on RBD positioning triggered by changes in the SD2 region, which harbors residue 614 and the furin cleavage site. Our results elucidate SARS-CoV-2 S conformational landscape and allostery and have implications for vaccine design.
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•SARS-CoV-2 S 2P mutations do not impact its structure, stability, or antigenicity•D614G mutation increases RBD “up” state and enhances S1/S2 junction proteolysis•Structure and antigenicity reveal allostery between the S1/S2 junction and RBD•SD2 anchors the mobile RBD and NTD, separating large S1 subunit motions from S2
SARS-CoV-2 spike undergoes large conformational changes during cell fusion. Gobeil et al. identify a subdomain anchor that limits large motions in the receptor binding subunit of the pre-fusion spike from propagating to its fusion subunit. They demonstrate that the D614G mutation increases the rate of furin cleavage, which may impact infectivity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Latency reversal and viral clearance to cure HIV-1 Margolis, David M.; Garcia, J. Victor; Hazuda, Daria J. ...
Science (American Association for the Advancement of Science),
07/2016, Volume:
353, Issue:
6297
Journal Article
Peer reviewed
Open access
Research toward a cure for human immunodeficiency virus type 1 (HIV-1) infection has joined prevention and treatment efforts in the global public health agenda. A major approach to HIV eradication ...envisions antiretroviral suppression, paired with targeted therapies to enforce the expression of viral antigen from quiescent HIV-1 genomes, and immunotherapies to clear latent infection. These strategies are targeted to lead to viral eradication--a cure for AIDS. Paired testing of latency reversal and clearance strategies has begun, but additional obstacles to HIV eradication may emerge. Nevertheless, there is reason for optimism that advances in long-acting antiretroviral therapy and HIV prevention strategies will contribute to efforts in HIV cure research and that the implementation of these efforts will synergize to markedly blunt the effect of the HIV pandemic on society.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
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