scholarly journals In the Era of mRNA Vaccines, Is There Any Hope for HIV Functional Cure?

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 501
Author(s):  
Ignasi Esteban ◽  
Carmen Pastor-Quiñones ◽  
Lorena Usero ◽  
Montserrat Plana ◽  
Felipe García ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Low Cost ◽  
Rapid Development ◽  
Research Field ◽  
Functional Cure ◽  
Promising Alternative ◽  
Hiv Antiretroviral Therapy ◽  
Hiv Acquisition ◽  
Hiv 1

Over 36 million people worldwide are infected with HIV. Antiretroviral therapy (ART) has proven to be highly effective to prevent HIV-1 transmission, clinical progression and death. Despite this success, the number of HIV-1 infected individuals continues increasing and ART should be taken for life. Therefore, there are two main priorities: the development of preventive vaccines to protect from HIV acquisition and achieve an efficient control of HIV infection in the absence of ART (functional cure). In this sense, in the last few years, there has been a broad interest in new and innovative approaches such as mRNA-based vaccines. RNA-based immunogens represent a promising alternative to conventional vaccines because of their high potency, capacity for rapid development and potential for low-cost manufacture and safe administration. Some mRNA-based vaccines platforms against infectious diseases have demonstrated encouraging results in animal models and humans. However, their application is still limited because the instability and inefficient in vivo delivery of mRNA. Immunogens, design, immunogenicity, chemical modifications on the molecule or the vaccine delivery methods are all crucial interventions for improvement. In this review we, will present the current knowledge and challenges in this research field. mRNA vaccines hold great promises as part of a combined strategy, for achieving HIV functional cure.

scholarly journals Strong In Vivo Inhibition of HIV-1 Replication by Nullbasic, a Tat Mutant

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Hongping Jin ◽  
Yifan Sun ◽  
Dongsheng Li ◽  
Min-Hsuan Lin ◽  
Mary Lor ◽  
...  
Keyword(s):  
Mutant Form ◽  
Mrna Levels ◽  
Functional Cure ◽  
Fold Reduction ◽  
Infected Cells ◽  
Hiv 1 ◽  
Transcription And Replication ◽  
In Cells

ABSTRACT Nullbasic is a mutant form of the HIV-1 transcriptional activator protein (Tat) that strongly inhibits HIV-1 transcription and replication in lymphocytes in vitro. To investigate Nullbasic inhibition in vivo, we employed an NSG mouse model where animals were engrafted with primary human CD4+ cells expressing a Nullbasic-ZsGreen1 (NB-ZSG) fusion protein or ZSG. NB-ZSG and ZSG were delivered by using a retroviral vector where CD4+ cells were transduced either prior to (preinfection) or following (postinfection) HIV-1 infection. The transduced cells were analyzed in vitro up to 10 days postinfection (dpi) and in vivo up to 39 dpi. Compared to ZSG, NB-ZSG strongly inhibited HIV-1 replication both in vitro and in vivo using preinfection treatment. In vitro, HIV-1 mRNA levels in cells were reduced by up to 60-fold. In vivo, HIV-1 RNA was undetectable in plasma samples during the course of the experiment, and HIV-1 mRNA levels in resident CD4+ cells in organ tissue were reduced up to 2,800-fold. Postinfection treatment of HIV-1-infected cells with NB-ZSG attenuated HIV-1 infection for up to 14 days. In vitro, a 25-fold reduction of viral mRNA in cells was observed but diminished to a <2-fold reduction by 10 dpi. In vivo, HIV-1 RNA was undetectable in plasma of NB-ZSG mice at 14 dpi but afterwards was not significantly different between NB-ZSG mice and control mice. However, we observed higher levels of CD4+ cells in NB-ZSG mice than in control mice, suggesting that NB-ZSG imparted a survival advantage to HIV-1-infected animals. IMPORTANCE HIV-1 infection is effectively controlled by antiviral therapy that inhibits virus replication and reduces viral loads below detectable levels in patients. However, therapy interruption leads to viral rebound due to latently infected cells, which serve as a source of continued viral infection. Interest in strategies leading to a functional cure for HIV-1 infection by long-term or permanent viral suppression is growing. Here, we show that a mutant form of the HIV-1 Tat protein, referred to as Nullbasic, inhibits HIV-1 transcription in infected CD4+ cells in vivo. Analysis shows that stable expression of Nullbasic in CD4+ cells could lead to durable anti-HIV-1 activity. Nullbasic, as a gene therapy candidate, could be a part of a functional-cure strategy to suppress HIV-1 transcription and replication.

Lipid-Based Vectors for Therapeutic mRNA-Based Anti-Cancer Vaccines

2019 ◽  
Vol 25 (13) ◽  
pp. 1443-1454 ◽  
Author(s):  
Maria L. Guevara ◽  
Stefano Persano ◽  
Francesca Persano
Keyword(s):  
Cancer Vaccines ◽  
Large Scale ◽  
Low Cost ◽  
Tumor Vaccines ◽  
Promising Alternative ◽  
Technological Advances ◽  
Anti Cancer ◽  
Anti Tumor Activity ◽  
In Vivo Delivery

Cancer vaccines have been widely explored as a key tool for effective cancer immunotherapy. Despite a convincing rationale behind cancer vaccines, extensive past efforts were unsuccessful in mediating significantly relevant anti-tumor activity in clinical studies. One of the major reasons for such poor outcome, among others, is the low immunogenicity of more traditional vaccines, such as peptide-, protein- and DNA- based vaccines. Recently, mRNA emerged as a promising alternative to traditional vaccine strategies due to its high immunogenicity, suitability for large-scale and low-cost production, and superior safety profile. However, the clinical application of mRNA-based anti-cancer vaccines has been limited by their instability and inefficient in vivo delivery. Recent technological advances have now largely overcome these issues and lipid-based vectors have demonstrated encouraging results as mRNA vaccine platforms against several types of cancers. This review intends to provide a detailed overview of lipid-based vectors for the development of therapeutic mRNA-based anti-tumor vaccines.

scholarly journals Bletilla striataMicron Particles Function as a Hemostatic Agent by Promoting Rapid Blood Aggregation

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Chen Zhang ◽  
Rui Zeng ◽  
Zhencheng Liao ◽  
Chaomei Fu ◽  
Hui Luo ◽  
...  
Keyword(s):  
Low Cost ◽  
In Vivo Studies ◽  
Hemostatic Agent ◽  
Severe Bleeding ◽  
Promising Alternative ◽  
Bletilla Striata ◽  
Visible Particle ◽  
Injury Model

The human body cannot control blood loss without treatment. Available hemostatic agents are ineffective at treating cases of severe bleeding and are expensive or raise safety concerns.Bletilla striataserve as an inexpensive, natural, and promising alternative. However, no detailed studies on its hemostatic approach have been performed. The aim of this study was to examine the hemostatic effects ofB. striataMicron Particles (BSMPs) and their hemostatic mechanisms. We prepared and characterized BSMPs of different size ranges and investigated their use as hemostatic agent. BSMPs of different size ranges were characterized by scanning electron microscope. In vitro coagulation studies revealed BSMP-blood aggregate formation via stereoscope and texture analyzers. In vivo studies based on rat injury model illustrated the BSMP capabilities under conditions of hemostasis. Compared to other BSMPs of different size ranges, BSMPs of 350–250 μm are most efficient in hemostasis. As powder sizes decrease, the degree of aggregation between particles and hemostatic BSMP effects declines. The BSMP in contact with a bleeding surface locally forms a visible particle/blood aggregate as a physical barrier that facilitates hemostasis. Considering the facile preparation, low cost, and long shelf life ofB. striata, BSMPs offer great potential as mechanisms of trauma treatment.

scholarly journals Deep sequence modelling for predicting COVID-19 mRNA vaccine degradation

2021 ◽  
Vol 7 ◽  
pp. e597
Author(s):  
Talal S. Qaid ◽  
Hussein Mazaar ◽  
Mohammed S. Alqahtani ◽  
Abeer A. Raweh ◽  
Wafaa Alakwaa
Keyword(s):  
Low Cost ◽  
Rapid Development ◽  
The Body ◽  
High Potency ◽  
Low Protein ◽  
Deep Model ◽  
The Difference ◽  
Encoding Method ◽  
In Vivo Delivery

The worldwide coronavirus (COVID-19) pandemic made dramatic and rapid progress in the year 2020 and requires urgent global effort to accelerate the development of a vaccine to stop the daily infections and deaths. Several types of vaccine have been designed to teach the immune system how to fight off certain kinds of pathogens. mRNA vaccines are the most important candidate vaccines because of their capacity for rapid development, high potency, safe administration and potential for low-cost manufacture. mRNA vaccine acts by training the body to recognize and response to the proteins produced by disease-causing organisms such as viruses or bacteria. This type of vaccine is the fastest candidate to treat COVID-19 but it currently facing several limitations. In particular, it is a challenge to design stable mRNA molecules because of the inefficient in vivo delivery of mRNA, its tendency for spontaneous degradation and low protein expression levels. This work designed and implemented a sequence deep model based on bidirectional GRU and LSTM models applied on the Stanford COVID-19 mRNA vaccine dataset to predict the mRNA sequences responsible for degradation by predicting five reactivity values for every position in the sequence. Four of these values determine the likelihood of degradation with/without magnesium at high pH (pH 10) and high temperature (50 degrees Celsius) and the fifth reactivity value is used to determine the likely secondary structure of the RNA sample. The model relies on two types of features, namely numerical and categorical features, where the categorical features are extracted from the mRNA sequences, structure and predicted loop. These features are represented and encoded by numbers, and then, the features are extracted using embedding layer learning. There are five numerical features depending on the likelihood for each pair of nucleotides in the RNA. The model gives promising results because it predicts the five reactivity values with a validation mean columnwise root mean square error (MCRMSE) of 0.125 using LSTM model with augmentation and the codon encoding method. Codon encoding outperforms Base encoding in MCRMSE validation error using the LSTM model meanwhile Base encoding outperforms codon encoding due to less over-fitting and the difference between the training and validation loss error is 0.008.

scholarly journals Current Knowledge on Honey and Its Derivatives with Genomic Stability: A Mini Review

2017 ◽  
Vol 9 (13) ◽  
pp. 145
Author(s):  
Malisanurhidayu Yaacob ◽  
Anne Jesscy Stanis ◽  
Nor Fadilah Rajab ◽  
Suzana Shahar ◽  
Razinah Sharif
Keyword(s):  
Dna Damage ◽  
Honey Bee ◽  
Royal Jelly ◽  
Current Knowledge ◽  
Genomic Stability ◽  
Research Field ◽  
Search Term ◽  
Bee Pollen

Genome health is an important factor that plays a role in various degenerative diseases. Instability of genome is the prevalence of mutation within the genome such as changed in nucleic acid and chromosomal arrangement and also the presence of abnormal number of chromosome in cell. Therefore, several method were used to overcome this problem and one of them is by using natural product such as honey, propolis, bee pollen and royal jelly that is high in antioxidant. Those are products that derive from honey bee and had been used as food supplement to increase the quality of life. Therefore, this systematic review provides the updates on the potential of honey bee products to decrease DNA damage both in in vivo and in vitro approaches. Search term of “honey”, “propolis”, “bee pollen”, royal jelly”, “DNA damage”, “genome integrity”, and “telomere” were used for searching purpose in three databases (Scopus, Pubmed and Medline) and also Google Scholar. All the published articles were assessed using PRISMA guidelines and finally after the eligibility process, only 34 published articles were selected for this review. Based on the reports, the product from the honey bee decrease the genome related diseases by reducing the accumulation of free radical, increase the DNA repair protein expression and decrease the telomerase activity in the cell. This provides a large gap in the research field focusing on the effect of those derivatives from bees on genomic stability.

scholarly journals An Overview on the Development of mRNA-Based Vaccines and Their Formulation Strategies for Improved Antigen Expression In Vivo

Vaccines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 244
Author(s):  
Md. Motiar Rahman ◽  
Nan Zhou ◽  
Jiandong Huang
Keyword(s):  
Animal Models ◽  
Low Cost ◽  
Antigen Expression ◽  
Future Perspectives ◽  
Vaccine Platform ◽  
High Potency ◽  
Promising Alternative ◽  
Vaccine Approach ◽  
Technological Improvements

The mRNA-based vaccine approach is a promising alternative to traditional vaccines due to its ability for prompt development, high potency, and potential for secure administration and low-cost production. Nonetheless, the application has still been limited by the instability as well as the ineffective delivery of mRNA in vivo. Current technological improvements have now mostly overcome these concerns, and manifold mRNA vaccine plans against various forms of malignancies and infectious ailments have reported inspiring outcomes in both humans and animal models. This article summarizes recent mRNA-based vaccine developments, advances of in vivo mRNA deliveries, reflects challenges and safety concerns, and future perspectives, in developing the mRNA vaccine platform for extensive therapeutic use.

scholarly journals Potential Utilization of APOBEC3-Mediated Mutagenesis for an HIV-1 Functional Cure

2021 ◽  
Vol 12 ◽  
Author(s):  
Terumasa Ikeda ◽  
Yuan Yue ◽  
Ryo Shimizu ◽  
Hesham Nasser
Keyword(s):  
T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Mutagenic Activity ◽  
Primary Source ◽  
Virus Infectivity ◽  
Functional Cure ◽  
Viral Reservoirs ◽  
Proviral Dna ◽  
Hiv 1

The introduction of combination antiretroviral therapy (cART) has managed to control the replication of human immunodeficiency virus type 1 (HIV-1) in infected patients. However, a complete HIV-1 cure, including a functional cure for or eradication of HIV-1, has yet to be achieved because of the persistence of latent HIV-1 reservoirs in adherent patients. The primary source of these viral reservoirs is integrated proviral DNA in CD4+ T cells and other non-T cells. Although a small fraction of this proviral DNA is replication-competent and contributes to viral rebound after the cessation of cART, &gt;90% of latent viral reservoirs are replication-defective and some contain high rates of G-to-A mutations in proviral DNA. At least in part, these high rates of G-to-A mutations arise from the APOBEC3 (A3) family proteins of cytosine deaminases. A general model has shown that the HIV-1 virus infectivity factor (Vif) degrades A3 family proteins by proteasome-mediated pathways and inactivates their antiviral activities. However, Vif does not fully counteract the HIV-1 restriction activity of A3 family proteins in vivo, as indicated by observations of A3-mediated G-to-A hypermutation in the proviral DNA of HIV-1-infected patients. The frequency of A3-mediated hypermutation potentially contributes to slower HIV-1/AIDS disease progression and virus evolution including the emergence of cytotoxic T lymphocyte escape mutants. Therefore, combined with other strategies, the manipulation of A3-mediated mutagenesis may contribute to an HIV-1 functional cure aimed at cART-free remission. In this mini-review, we discuss the possibility of an HIV-1 functional cure arising from manipulation of A3 mutagenic activity.

scholarly journals The HIV-1 Antisense Gene ASP: The New Kid on the Block

Vaccines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 513
Author(s):  
Zahra Gholizadeh ◽  
Mohd. Shameel Iqbal ◽  
Rui Li ◽  
Fabio Romerio
Keyword(s):  
Current Knowledge ◽  
Genomic Region ◽  
Antisense Gene ◽  
Rev Response Element ◽  
Glycoprotein Gene ◽  
Highly Hydrophobic ◽  
The Many ◽  
Reading Frames ◽  
Hiv 1

Viruses have developed incredibly creative ways of making a virtue out of necessity, including taking full advantage of their small genomes. Indeed, viruses often encode multiple proteins within the same genomic region by using two or more reading frames in both orientations through a process called overprinting. Complex retroviruses provide compelling examples of that. The human immunodeficiency virus type 1 (HIV-1) genome expresses sixteen proteins from nine genes that are encoded in the three positive-sense reading frames. In addition, the genome of some HIV-1 strains contains a tenth gene in one of the negative-sense reading frames. The so-called Antisense Protein (ASP) gene overlaps the HIV-1 Rev Response Element (RRE) and the envelope glycoprotein gene, and encodes a highly hydrophobic protein of ~190 amino acids. Despite being identified over thirty years ago, relatively few studies have investigated the role that ASP may play in the virus lifecycle, and its expression in vivo is still questioned. Here we review the current knowledge about ASP, and we discuss some of the many unanswered questions.

A technique for protecting delicate specimens during processing

1989 ◽  
Vol 47 ◽  
pp. 982-983
Author(s):  
R.J. Mount ◽  
R.V. Harrison
Keyword(s):  
Basilar Membrane ◽  
Low Cost ◽  
Organ Of Corti ◽  
Region Of Interest ◽  
Sensory Epithelium ◽  
Physical Damage ◽  
Air Drying ◽  
Specimen Handling ◽  
Two Component

The sensory end organ of the ear, the organ of Corti, rests on a thin basilar membrane which lies between the bone of the central modiolus and the bony wall of the cochlea. In vivo, the organ of Corti is protected by the bony wall which totally surrounds it. In order to examine the sensory epithelium by scanning electron microscopy it is necessary to dissect away the protective bone and expose the region of interest (Fig. 1). This leaves the fragile organ of Corti susceptible to physical damage during subsequent handling. In our laboratory cochlear specimens, after dissection, are routinely prepared by the O-T- O-T-O technique, critical point dried and then lightly sputter coated with gold. This processing involves considerable specimen handling including several hours on a rotator during which the organ of Corti is at risk of being physically damaged. The following procedure uses low cost, readily available materials to hold the specimen during processing ,preventing physical damage while allowing an unhindered exchange of fluids.Following fixation, the cochlea is dehydrated to 70% ethanol then dissected under ethanol to prevent air drying. The holder is prepared by punching a hole in the flexible snap cap of a Wheaton vial with a paper hole punch. A small amount of two component epoxy putty is well mixed then pushed through the hole in the cap. The putty on the inner cap is formed into a “cup” to hold the specimen (Fig. 2), the putty on the outside is smoothed into a “button” to give good attachment even when the cap is flexed during handling (Fig. 3). The cap is submerged in the 70% ethanol, the bone at the base of the cochlea is seated into the cup and the sides of the cup squeezed with forceps to grip it (Fig.4). Several types of epoxy putty have been tried, most are either soluble in ethanol to some degree or do not set in ethanol. The only putty we find successful is “DUROtm MASTERMENDtm Epoxy Extra Strength Ribbon” (Loctite Corp., Cleveland, Ohio), this is a blue and yellow ribbon which is kneaded to form a green putty, it is available at many hardware stores.

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