Nanokosmokseen saavuttu ja uutta rokotekehittelyä mahdollistuu exosomitasolta

https://www.ncbi.nlm.nih.gov/pubmed/29274250

Biotechnol J. 2018 Apr;13(4):e1700443. doi: 10.1002/biot.201700443. Epub 2018 Mar 24.

An Exosome-Based Vaccine Platform Imparts Cytotoxic T Lymphocyte Immunity Against Viral Antigens.Anticoli S¹, Manfredi F¹, Chiozzini C¹, Arenaccio C¹, Olivetta E¹, Ferrantelli F¹, Capocefalo A², Falcone E², Ruggieri A², Federico M¹. Abstract

Exosomes are 50-150 nm sized nanovesicles released by all eukaryotic cells. The authors very recently described a method to engineer exosomes in vivo with the E7 protein of Human Papilloma Virus (HPV). This technique consists in the intramuscular injection of a DNA vector expressing HPV-E7 fused at the C-terminus of an exosome-anchoring protein, that is, Nef^mut , the authors previously characterized for its high levels of incorporation in exosomes. In this configuration, the ≈11 kDa E7 protein elicited a both strong and effective antigen-specific cytotoxic T lymphocyte (CTL) immunity. Attempting to establish whether this method could have general applicability, the authors expanded the immunogenicity studies toward an array of viral products of various origin and size including Ebola Virus VP24, VP40 and NP, Influenza Virus NP, Crimean-Congo Hemorrhagic Fever NP, West Nile Virus NS3, and Hepatitis C Virus NS3. All antigens appeared stable upon fusion with Nef^mut , and are uploaded in exosomes at levels comparable to Nef^mut . When injected in mice, DNA vectors expressing the diverse fusion products elicited a well detectable antigen-specific CD8⁺ T cell response associating with a cytotoxic activity potent enough to kill peptide-loaded and/or antigen-expressing syngeneic cells. These data definitely proven both effectiveness and flexibility of this innovative CTL vaccine platform. KEYWORDS:

CTL immunity; DNA immunization; Ebola virus; HIV-1 Nef; exosomes


(2) 
https://www.ncbi.nlm.nih.gov/pubmed/30167966 

Mol Biotechnol. 2018 Nov;60(11):773-782. doi: 10.1007/s12033-018-0114-3.

DNA Vectors Generating Engineered Exosomes Potential CTL Vaccine Candidates Against AIDS, Hepatitis B, and Tumors. Ferrantelli F¹, Manfredi F¹, Chiozzini C¹, Anticoli S¹, Olivetta E¹, Arenaccio C¹, Federico M². Abstract

Eukaryotic cells constitutively produce nanovesicles of 50-150 nm of diameter, referred to as exosomes, upon release of the contents of multivesicular bodies (MVBs). We recently characterized a novel, exosome-based way to induce cytotoxic T lymphocyte (CTL) immunization against full-length antigens. It is based on DNA vectors expressing products of fusion between the exosome-anchoring protein Nef mutant (Nef^mut) with the antigen of interest. The strong efficiency of Nef^mut to accumulate in MVBs results in the production of exosomes incorporating huge amounts of the desired antigen. When translated in animals, the injection of Nef^mut-based DNA vectors generates engineered exosomes whose internalization in antigen-presenting cells induces cross-priming and antigen-specific CTL immunity. Here, we describe the molecular strategies we followed to produce DNA vectors aimed at generating immunogenic exosomes potentially useful to elicit a CTL immune response against antigens expressed by the etiologic agents of major chronic viral infections, i.e., HIV-1, HBV, and the novel tumor-associated antigen HOXB7. Unique methods intended to counteract intrinsic RNA instability and nuclear localization of the antigens have been developed. The success we met with the production of these engineered exosomes opens the way towards pre-clinic experimentations devoted to the optimization of new vaccine candidates against major infectious and tumor pathologies. KEYWORDS:

Constitutive transport elements; Exosomes; HBV; HIV-1; HOXB7; Nef

PMID:

30167966

DOI:

10.1007/s12033-018-0114-3

[Indexed for MEDLINE]

Exosomit apuna fulevaisuuden rokotteissa viruksia vastaan

 https://www.ncbi.nlm.nih.gov/pubmed/30167966

Mol Biotechnol. 2018 Nov;60(11):773-782. doi: 10.1007/s12033-018-0114-3.

DNA Vectors Generating Engineered Exosomes Potential CTL Vaccine Candidates Against AIDS, Hepatitis B, and Tumors.Ferrantelli F¹, Manfredi F¹, Chiozzini C¹, Anticoli S¹, Olivetta E¹, Arenaccio C¹, Federico M².  Abstract

Eukaryotic cells constitutively produce nanovesicles of 50-150 nm of diameter, referred to as exosomes, upon release of the contents of multivesicular bodies (MVBs).

We recently characterized a novel, exosome-based way to induce cytotoxic T lymphocyte (CTL) immunization against full-length antigens. It is based on DNA vectors expressing products of fusion between the exosome-anchoring protein Nef mutant (Nef^mut) with the antigen of interest. The strong efficiency of Nef^mut to accumulate in MVBs results in the production of exosomes incorporating huge amounts of the desired antigen. When translated in animals, the injection of Nef^mut-based DNA vectors generates engineered exosomes whose internalization in antigen-presenting cells induces cross-priming and antigen-specific CTL immunity.

Here, we describe the molecular strategies we followed to produce DNA vectors aimed at generating immunogenic exosomes potentially useful to elicit a CTL immune response against antigens expressed by the etiologic agents of major chronic viral infections, i.e., HIV-1, HBV, and the novel tumor-associated antigen HOXB7.
 Unique methods intended to counteract intrinsic RNA instability and nuclear localization of the antigens have been developed. The success we met with the production of these engineered exosomes opens the way towards pre-clinic experimentations devoted to the optimization of new vaccine candidates against major infectious and tumor pathologies.

HIV-1 infektioituneen solun exosomi edistää syöpiä NADC

https://www.ncbi.nlm.nih.gov/pubmed/30389917

Nat Commun. 2018 Nov 2;9(1):4585. doi: 10.1038/s41467-018-07006-2.

Exosomes derived from HIV-1-infected cells promote growth and progression of cancer via HIV TAR RNA. Chen L¹, Feng Z¹, Yue H^1,2, Bazdar D³, Mbonye U⁴, Zender C^5,6, Harding CV^6,7,8, Bruggeman L^8,9, Karn J^4,6,8, Sieg SF^3,8, Wang B^6,10, Jin G^11,12,13. Abstract

Suomennosta abstraktista 20.12. 2018.
Antiretrovirusterapiaa saavilla HIV/AIDS -potilailla  on lisääntynyttä riskiä NADC- tyyppisistä syövistä  (Non- AIDS-defining cancer). Kuitenkin on ollut epäselvää, mikä on  taustamekanismi tiettyjen NADS- syöpien  kehittymiselle ja progredioitumsielle.   Tässä artikkelissa  osoitetaan, että HIV-infektoituneista T-soluissa  vapautuneet  exosomit  sekä   HIV-positiivisten  potilaiden verestä puhdistetut exosomit stimuloivat  oro/orofaryngeaalisten syöpäsolujen  ja keuhkosyöpäsolujen  proliferaatiota, migraatiota ja invaasiota. HIV-infektoituneitten T-solujen  syöpäsoluproliferaatiota  edistävä tekijä on  HIV:n  TAR (transaktivaatiovaste-elementti)-RNA ja se indusoi proto-onkogeenien ilmenemistä  sekä  Tollin-reseptorien kaltaisilla   reseptoreilla indusoituvien geenien ilmenemistä.  Nämä vaikutukset riippuvat  molekyylin  rakenteellisista seikoista ( loop/bulge region , silmukka/esiintyöntymäkohta ). HIV-infektoituneitten T-solujen exosomit  menevät  nopeasti vastaanottavaan soluun epidermaalisen kasvutekijän reseptorin (EGFR)  kautta  ja stimuloivat ERK1/2 fosforylaatiota ja EGFR/TLR3-akselia  Täten tutkijoiden löydöt viittaavat siihen, että  TAR- RNA-pitoiset eksosomit HIV-infektoituneista T-soluista edistävät  tiettyjen NADC- syöpien kasvua ja progredioitumista  aktivoimalla  ERK- ketjureaktion EGFR/TLR3:sta riippuvalla tavalla.

• People living with HIV/AIDS on antiretroviral therapy have increased risk of non-AIDS-defining cancers (NADCs). However, the underlying mechanism for development and progression of certain NADCs remains obscure. Here we show that exosomes released from HIV-infected T cells and those purified from blood of HIV-positive patients stimulate proliferation, migration and invasion of oral/oropharyngeal and lung cancer cells. The HIV transactivation response (TAR) element RNA in HIV-infected T-cell exosomes is responsible for promoting cancer cell proliferation and inducing expression of proto-oncogenes and Toll-like receptor 3 (TLR3)-inducible genes. These effects depend on the loop/bulge region of the molecule. HIV-infected T-cell exosomes rapidly enter recipient cells through epidermal growth factor receptor (EGFR) and stimulate ERK1/2 phosphorylation via the EGFR/TLR3 axis. Thus, our findings indicate that TAR RNA-containing exosomes from HIV-infected T cells promote growth and progression of particular NADCs through activation of the ERK cascade in an EGFR/TLR3-dependent manner.

PMID:

30389917

PMCID:

PMC6214989

DOI:

10.1038/s41467-018-07006-2

Free PMC Article

Muistiinpanoja  Mef  Nilbert- kirjasta: 

MÅLSTRUKTUR  EGFR;   

Ca tyyppi:  huvud, hals cancer   skivepitel  Preparat: Cetuximab

Ca tyyppi: Lung cancer:  erlotinib 

Ca tyyppi CRC: panitumumab.

Exosomit ja HIV-1 virus

https://www.ncbi.nlm.nih.gov/pubmed/29687643

Proteomics Clin Appl. 2018 Sep;12(5):e1700142. doi: 10.1002/prca.201700142. Epub 2018 May 21.

Proteomic Analysis of Exosomes and Its Application in HIV-1 Infection. Cheruiyot C¹, Pataki Z¹, Ramratnam B^1,2,3, Li M¹. Abstract

 Suomennosta abstraktista  20.12. 2018 :
EXOSOMIT, extrasellulaariset eriterakkulat,  ovat 30 -100 nanometriä  läpimitaltaan ja niitä muodostuu myöhäisistä endosomeista erityyppisistä soluista. Lukuisat exosomeja käsittelevät tutkimukset viitatavat siihen, että HIV-1 viruksen biogeneesissä on exosomeilla merkitsevää osaa. Proteomitutkimukset kombinoituna  exosomien fraktiointiin ovat olleet menestyksekäs  menetelmä erilaisten exosomaalisten proteiinien tunnistamiseksi  ja auttaneet  myös  paljastamaan exosomien ja HIV-1:n välisiä interaktioita.
Tässä katsauksessa valaistaan nykyistä kehitystä erilaisissa  exosomieristys- ja  puhdistamismetodeissa ja   niiden sovelluksissa HIV-1-tutkimuksiin. 
Punnitaan erilaisten proteomitekniikoiden osuutta exosomien sisällön määrittelyssä.
Pohditaan  proteomien ja exosomien tutkimuksellisia ja kliinisiä sovellutuksia  HIV-1 viruksen  biologiaan.

( Koko artikkeli on hankittavissa  linkistä) 

• Exosomes are 30-100 nm extracellular vesicles secreted from late endosomes by various types of cells. Numerous studies have suggested that exosomes play significant roles in human immunodeficiency virus 1 (HIV-1) biogenesis. Proteomics coupled with exosome fractionation has been successfully used to identify various exosomal proteins and helped to uncover the interactions between exosomes and HIV-1. 
• To inform the current progress in the intersection of exosome, proteomics, and HIV-1, this review is focused on: i) analyzing different exosome isolation, purification methods, and their implications in HIV-1 studies; ii) evaluating the roles of various proteomic techniques in defining exosomal contents; iii) discussing the research and clinical applications of proteomics and exosome in HIV-1 biology.

PMID:

29687643

DOI:

10.1002/prca.201700142

Retrovirologian moderneimpien lääkkeiden (INSTI) ongelmia on resisitenssin muodosotus .

Ihmiskehon  geenivarastoss on mahdollisia antiretroviraaleja proeiineja. niiden esiinherättäminen on yksimahdollinen tie, muat se vaatii ahkeran genomitutkimustieteen, että tämä valtava arsenaali saadaan muovauspöydälle.
(Yksi tällainen tekijä TRIM28 (KAP1, TIFB) on  integraasin estäjä funktioltaan. tästä erikseen edellä).
HIV-1 integraasin(IN) esto  tarkoitaa käytännössä sitä, että estetään virusta saamasta oma provirusmateriaalinsa integroiduksi ihmisen genomiin.
On kehitelty  viruksen  intrgoitumisen estämiseksi lääkkeitä,  INSTI- ryhmä. ( Integration strand trnasfer inhibitors). niistä täässä alla artikkeli vuodelta 2017. otaten huomioon että HIV-1 virus menee hyvin varhain neurologiseen kudokseen  ja aivoon ja suoritaa integraatiota,  integraasin eston tulisi tapahtua varhain.

 https://retrovirology.biomedcentral.com/articles/10.1186/s12977-017-0360-7

HIV drug resistance against strand transfer integrase inhibitors

Kaitlin Anstett,
Bluma Brenner,
Thibault MespledeEmail authorView ORCID ID profile and
Mark A. Wainberg^

^Deceased

Retrovirology201714:36

https://doi.org/10.1186/s12977-017-0360-7

©  The Author(s) 2017

Received: 15 May 2017
Accepted: 30 May 2017
Published: 5 June 2017

 Abstract

SUOMENNOSTA:

Integrase strand transfer inhibitors (INSTIs) are the newest class of antiretroviral drugs to be approved for treatment and act by inhibiting the essential HIV protein integrase from inserting the viral DNA genome into the host cell’s chromatin. Three drugs of this class are currently approved for use in HIV-positive individuals: raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG), while cabotegravir (CAB) and bictegravir (BIC) are currently in clinical trials. RAL and EVG have been successful in clinical settings but have relatively low genetic barriers to resistance. Furthermore, they share a high degree of cross-resistance, which necessitated the development of so-called second-generation drugs of this class (DTG, CAB, and BIC) that could retain activity against these resistant variants. In vitro selection experiments have been instrumental to the clinical development of INSTIs, however they cannot completely recapitulate the situation in an HIV-positive individual. This review summarizes and compares all the currently available information as it pertains to both in vitro and in vivo selections with all five INSTIs, and the measured fold-changes in resistance of resistant variants in in vitro assays. While the selection of resistance substitutions in response to RAL and EVG bears high similarity in patients as compared to laboratory studies, there is less concurrence regarding the “second-generation” drugs of this class. This highlights the unpredictability of HIV resistance to these inhibitors, which is of concern as CAB and BIC proceed in their clinical development.

Background

Since the beginning of the pandemic, HIV/AIDS has claimed the lives of over 35 million people, and approximately 35 million individuals are currently infected [1]. Highly active antiretroviral therapy (HAART) has transformed a positive HIV diagnosis from a former death sentence into a chronic, manageable disease. However, no cure yet exists for HIV and patients must remain on therapy for the entirety of their lives which makes the development of drug resistance in the virus a real concern. In fact, drug resistance has been documented for every currently available drug class in patients [2]. This makes the continued study of the mechanisms of HIV drug resistance and novel therapeutics a top priority for HIV scientists worldwide.

The reverse transcriptase (RT) enzyme of HIV is highly error-prone, introducing mutations into the genome at a rate of 1.4 × 10⁻⁵ mutation per base pair, per replication cycle [3]. This high mutation rate allows for the generation of multiple different viruses within an infected individual, sometimes referred to as “quasi-species.” If one of these quasi-species has a mutation that provides a selective advantage for replication in the presence of antiretrovirals (ARVs), it will out-compete other viral forms to become the dominant species [4].

 The integrase (IN) enzyme catalyses the insertion of the viral DNA (vDNA) into the host’s genome through two catalytic actions: 3′ processing and strand transfer. In the cytoplasm, IN self-associates into tetramers on the newly reverse transcribed vDNA, where it catalyzes the removal of the last two nucleotides from the 3′ ends of both strands [5]. In addition, IN can spontaneously form larger multimers that are stabilized by the addition of allosteric integrase inhibitors, and reciprocally destabilized in the presence of DNA [6, 7, 8, 9, 10]. After nuclear translocation, IN associates with lens epithelium-derived growth factor (LEDGF)/p75 and is directed to sites of open chromatin, where it will initiate strand transfer, i.e. the nucleophilic attack of the 3′ hydroxyl groups on the viral DNA on the nucleotide backbone of the host DNA. The integration process is completed by host gap-repair machinery, resulting in a 5 base-pair repeat that flanks each end of the viral DNA [11].

The integrase strand transfer inhibitor (INSTI) class of antiretroviral drugs is the latest to be approved for treatment of HIV-positive individuals. As their name suggest, INSTIs inhibit the second step catalyzed by IN, i.e. strand transfer, through competitive binding to the enzyme’s active site. INSTIs not only displace the 3′ end of the vDNA from the active site, but also chelate the divalent cation (Mg²⁺ or Mn²⁺) that is required for IN enzymatic activity [12]. There are currently three INSTIs approved for the treatment of HIV infection: raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) [13]. Cabotegravir (CAB) and bictegravir (BIC) are newer INSTIs currently in clinical trials [14,15)

Although highly efficacious in the management of HIV, both RAL and EVG are susceptible to virological failure through the development of resistance mutations. What is more, most of the changes that cause resistance to RAL also cause resistance to EVG, and vice versa [16]. This is, however, not the case with DTG. Not only does DTG appear to have a higher genetic barrier to resistance than either of the other two drugs, it has not yet been shown to definitively select for any resistance-associated changes in treatment-naïve patients [17]. Although two reports of potential emergence of resistance in individuals treated with DTG in first line therapy recently appeared, baseline IN was not sequenced in one of these cases, nor did the supposed-emergent mutation lead to persistent virological failure while DTG was still being used together with an optimized background regimen containing rilpivirine (RPV), an NNRTI with a modest genetic barrier to resistance [18]. Specifically, initial TDF/FTC/DTG treatment was supplemented with ritonavir-boosted darunavir following failure; the latter drug was subsequently substituted with RPV for reason of diffuse erythoderma. The second case reported transient emergence of a T97A substitution that did not confer any resistance on its own against DTG in vitro and was not observed at subsequent time points [19]. Although it cannot be excluded that unambiguously documented cases of emergent resistance mutations against first-line DTG will eventually be reported, it is expected that this will be rare. This is supported by the fact that despite dolutegravir being used by tens of thousands treatment-naïve individuals in Europe and the USA, the abovementioned two cases are the only known reports of potential primary de novo resistance against this drug. There have also been rare cases of treatment failure with resistance mutations in treatment-experienced but INSTI-naïve patients, and, in this setting, DTG has most often selected for the novel resistance substitution R263K [20]. Other substitutions at residues E92, Q148 and N155, have been reported when DTG monotherapy was used in treatment-experienced patients.

Primary resistance substitutions arise first in response to INSTI drug pressure and cause a decrease in susceptibility at the expense of viral fitness, most often through alterations to the enzyme’s active site where the inhibitors bind [16, 21]. Secondary resistance substitutions arise after continued drug pressure and usually act to alleviate the negative effects of primary mutations, and may also increase levels of INSTI resistance [22, 23]. Some of these secondary changes are specific to a certain primary resistance pathway, but many may be selected after several different primary mutations.

 Pre-clinical and in vitro studies have been instrumental in the evaluation of novel therapeutic agents for the treatment of HIV infection, however they do not always accurately predict clinical outcomes for patients. Laboratory viral strains and cell lines, although excellent scientific tools, can never recapitulate in vivo human infections with 100% accuracy. In this review, we compare both the in vitro selection and antiviral activity reported for drugs of the INSTI class with the analogous data available from treated patients to assess the predictive power of in vitro studies for INSTI clinical outcomes.

Raltegravir

In 2004 a group of researchers at Merck & Co. reported on the efficacy of the diketo acid (DKA)-based lead compound L-870812 against simian immunodeficiency virus (SIV) in infected rhesus macaques [24]. This led to the approval of the first INSTI, raltegravir, in 2007 for treatment-experienced AIDS patients with multidrug resistance, and two years later for treatment-naïve individuals as well [25, 26]. In the 10 years since its first approval, RAL has been shown to be well tolerated in the vast majority of patients, although it is does require twice daily dosing. It displays a modest genetic barrier to resistance, with the most common mutational pathways consisting of changes at positions Y143, Q148, and N155 [27].......( more  information in the link) 

Elvitegravir

EVG is a monoketo acid derivative that also demonstrated high specificity for inhibition of HIV IN strand transfer reactions [77]. EVG was developed by Gilead Sciences and approved for use in HIV infected individuals in 2012 [26]. Because EVG is processed by the cytochrome p450 enzyme CYP3A4/5, it needs to be co-formulated with cobicistat to boost plasma concentrations. This permits once daily dosing of EVG [78].

It is evident from both Tables 3.........( More information  in the link) 

Second-generation INSTIs

The relatively low genetic barrier and high degree of cross-resistance among the so called “first-generation” INSTIs RAL and EVG spurred research into the chase for “second-generation” drugs of this class, aimed at retaining efficacy against RAL/EVG resistant variants. There have been four candidate second-generation INSTIs to date. DTG, manufactured by ViiV-Healthcare and GlaxoSmithKline, was approved in 2013 for both treatment-naïve and—experienced patients and is the only second-generation INSTI to be approved to date [79]. MK-2048 showed potent activity against most RAL/EVG resistant variants and did not select for the same substitutions in tissue culture studies but its clinical development was halted due to poor pharmacokinetics. Both CAB and BIC are promising and both are currently in advanced clinical trials [15, 19, 50, 80].

( More info in the link...) 

There are fewer reports on the resistance patterns of CAB, a novel INSTI under development at GlaxoSmithKline. CAB was developed concomitantly with DTG and shares most of its structure; it has the potential to be formulated as a long acting injectable for both pre-exposure prophylaxis and treatment of HIV infection [84]. In the LATTE clinical trial, one patient in the CAB arm did develop a mutation in the Q148 pathway, which suggests that this second-generation INSTI may select for the same mutations as RAL and EVG [15]. In in vitro selection studies, CAB has selected for changes at positions 146 and 153 that could also be selected in the presence of EVG and DTG, respectively (Table 4).

(More info in the link) 

TRIM28, joka rajoittaa HIV-1 integraasia : TRIM2((KAP1):n taistelusta HIV-1:täv astaan.

 https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(11)00168-5?code=cell-site


The integration of viral cDNA into the host genome is a critical step in the life cycle of HIV-1. This step is catalyzed by integrase (IN), a viral enzyme that is positively regulated by acetylation via the cellular histone acetyl transferase (HAT) p300. To investigate the relevance of IN acetylation, we searched for cellular proteins that selectively bind acetylated IN and identified KAP1, a protein belonging to the TRIM family of antiviral proteins. KAP1 binds acetylated IN and induces its deacetylation through the formation of a protein complex which includes the deacetylase HDAC1. Modulation of intracellular KAP1 levels in different cell types including T cells, the primary HIV-1 target, revealed that KAP1 curtails viral infectivity by selectively affecting HIV-1 integration. This study identifies KAP1 as a cellular factor restricting HIV-1 infection and underscores the relevance of IN acetylation as a crucial step in the viral infectious cycle.

Protein interactions

Protein	Gene	Interaction	Pubs
Envelope surface glycoprotein gp120	env	Tandem affinity purification and mass spectrometry analysis identify tripartite motif containing 28 (TRIM28), HIV-1 Gag, Gag/Pol, gp120, and Nef incorporated into staufen1 RNP complexes isolated from HIV-1-expressing cells	PubMed
Gag-Pol	gag-pol	Tandem affinity purification and mass spectrometry analysis identify tripartite motif containing 28 (TRIM28), HIV-1 Gag, Gag/Pol, gp120, and Nef incorporated into staufen1 RNP complexes isolated from HIV-1-expressing cells	PubMed
Nef	nef	Tandem affinity purification and mass spectrometry analysis identify tripartite motif containing 28 (TRIM28), HIV-1 Gag, Gag/Pol, gp120, and Nef incorporated into staufen1 RNP complexes isolated from HIV-1-expressing cells	PubMed
Pr55(Gag)	gag	Tandem affinity purification and mass spectrometry analysis identify tripartite motif containing 28 (TRIM28), HIV-1 Gag, Gag/Pol, gp120, and Nef incorporated into staufen1 RNP complexes isolated from HIV-1-expressing cells	PubMed
integrase	gag-pol	KAP1 inhibits HIV-1 integration via HIV-1 IN acetylation-dependent mechanism through HDAC1	PubMed
	gag-pol	The interaction between HIV-1 IN and KAP1 is highly favored by HAT/p300-mediated IN acetylation	PubMed

Go to the HIV-1, Human Interaction Database 


HIV_1 integraasin inhibiittoreita on kehitelty.
 

2016: Progress in HIV-1 Integrase Inhibitors: A Review of their Chemical Structure Diversity

Zahra Hajimahdi and Afshin Zarghi^*

Author information Article notes Copyright and License information Disclaimer

HIV-1 integrase (IN) enzyme, one of the three main enzymes of HIV-1, catalyzed the insertion of the viral DNA into the genome of host cells. Because of the lack of its homologue in human cells and its essential role in HIV-1 replication, IN inhibition represents an attractive therapeutic target for HIV-1 treatment. Since identification of IN as a promising therapeutic target, a major progress has been made, which has facilitated and led to the approval of three drugs. This review focused on the structural features of the most important IN inhibitors and categorized them structurally in 10 scaffolds. We also briefly discussed the structural and functional properties of HIV-1 IN and binding modes of IN inhibitors. The SAR analysis of the known IN inhibitors provides some useful clues to the possible future discovery of novel IN inhibitors.

Key Words: HIV-1, Integrase enzyme, SAR, Molecular diversity, IN Inhibitors

IN inhibitors are consisting of two main classes: integrase strand transfer inhibitors (INSTIs) and protein–protein interaction inhibitors (PPIIs). INSTIs target the enzyme active site, and the FDA-approved IN inhibitors are all INSTIs. IN catalyzes the incorporation of viral DNA into the host chromatin on interactions with various cellular proteins, such as lens epithelium-derived growth factor (LEDGF)/p75. LEDGINs which act as inhibitors of the LEDGF/p75–integrase interaction have been substantially developed in recent years (8-12).

In this review, we provided an insight to the structure and function of HIV-1 IN and its role in HIV-1 replication. We also highlighted progress medicinal chemistry efforts have made to date on IN inhibitors.

 

IN inhibitors are consisting of two main classes: integrase strand transfer inhibitors (INSTIs) and protein–protein interaction inhibitors (PPIIs). INSTIs target the enzyme active site, and the FDA-approved IN inhibitors are all INSTIs. IN catalyzes the incorporation of viral DNA into the host chromatin on interactions with various cellular proteins, such as lens epithelium-derived growth factor (LEDGF)/p75. LEDGINs which act as inhibitors of the LEDGF/p75–integrase interaction have been substantially developed in recent years (8-12).

In this review, we provided an insight to the structure and function of HIV-1 IN and its role in HIV-1 replication. We also highlighted progress medicinal chemistry efforts have made to date on IN inhibitors.

Figure 2

HIV-1 retroviral replication cycle (derived from 22).

 PMC full text:

Iran J Pharm Res. 2016 Autumn; 15(4): 595–628.

Copyright/LicenseRequest permission to reuse

 

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KAP1 trim28 PROTEIINIIN VAIIKUTTAA  myös sirtuiinin DEASEYLAATIOFUNKTIO. 

.

PLoS One. 2015 Apr 23;10(4):e0123935. doi: 10.1371/journal.pone.0123935. eCollection 2015.

KAP1 Deacetylation by SIRT1 Promotes Non-Homologous End-Joining Repair.

Lin YH¹, Yuan J², Pei H³, Liu T⁴, Ann DK⁵, Lou Z⁴.

Abstract

Homologous recombination and non-homologous end joining are two major DNA double-strand-break repair pathways. While HR-mediated repair requires a homologous sequence as the guiding template to restore the damage site precisely, NHEJ-mediated repair ligates the DNA lesion directly and increases the risk of losing nucleotides. Therefore, how a cell regulates the balance between HR and NHEJ has become an important issue for maintaining genomic integrity over time. Here we report that SIRT1-dependent KAP1 deacetylation positively regulates NHEJ. We show that up-regulation of KAP1 attenuates HR efficiency while promoting NHEJ repair. Moreover, SIRT1-mediated KAP1 deacetylation further enhances the effect of NHEJ by stabilizing its interaction with 53BP1, which leads to increased 53BP1 focus formation in response to DNA damage. Taken together, our study suggests a SIRT1-KAP1 regulatory mechanism for HR-NHEJ repair pathway choice. PMID: 25905708 PMCID:PMC4408008 DOI: 10.1371/journal.pone.0123935[Indexed for MEDLINE]Free PMC Article

 

Curr Drug Targets. 2013 Jun 1;14(6):648-52.

Sirtuin-1 and HIV-1: an overview.

Pinzone MR¹, Cacopardo B, Condorelli F, Di Rosa M, Nunnari G

Abstract

Sirtuins are a family of NAD+-dependent protein deacetylases, which regulate cell survival and energy metabolism, inflammation and cancer. Recent studies have shown that sirtuin-1 (SIRT1) modulates Human Immunodeficiency Virus (HIV)-1 transcription. The HIV-1 Tat protein is a substrate for the deacetylase activity of SIRT1; SIRT1 recycles Tat to its unacetylated form, catalyzing a fundamental step to start new cycles of viral transcription. Moreover, Tat has been reported to promote T-cell hyperactivation by suppressing SIRT1 activity. In fact, Tat blocks the ability of SIRT1 to deacetylate lysine 310 in the p65 subunit of nuclear factor- κB (NF- κB) by interacting with the deacetylase domain of SIRT1. This mechanism leads therefore to the hyperactivation of NF- κB proinflammatory pathway and may likely contribute to the chronic immune activation state of HIV-infected individuals. In the present review we first briefly describe the biological functions of sirtuins, then we delineate the interplay between SIRT1 and HIV-1 and discuss the potential role of SIRT1 as a pharmacological target of HIV-1 replication.

PMID:

23547809

[Indexed for MEDLINE]

Influenssarokotuksen antotekniikasta on opetusvideoita

https://www.youtube.com/watch?v=jmrSyyUSPNM
On tärkeä että rokotus ei ole mikään nivleruiske tai jännepisto vaan osuu olkavarren lihakseen, kuten kuva osoittaa;   Acromionin alapuolelle kaksi sormenleveyttä. 

Luonnollinen imuunivaste ja HIV-1 . Artikkeleita.

Löytöjä 3.12. 2018

Vuodelta 2008 
https://www.ncbi.nlm.nih.gov/pubmed/18187620

Science. 2008 Feb 15;319(5865):921-6. doi: 10.1126/science.1152725. Epub 2008 Jan 10.

Identification of host proteins required for HIV infection through a functional genomic screen.

Brass AL¹, Dykxhoorn DM, Benita Y, Yan N, Engelman A, Xavier RJ, Lieberman J, Elledge SJ.Abstract

HIV-1 exploits multiple host proteins during infection. We performed a large-scale small interfering RNA screen to identify host factors required by HIV-1 and identified more than 250 HIV-dependency factors (HDFs). These proteins participate in a broad array of cellular functions and implicate new pathways in the viral life cycle.

Further analysis revealed previously unknown roles for

•  retrograde Golgi transport proteins (Rab6 and Vps53) in viral entry, 
• a karyopherin (TNPO3) in viral integration, and 
• the Mediator complex (Med28) in viral transcription. 
• Transcriptional analysis revealed that HDF genes were enriched for high expression in immune cells, suggesting that viruses evolve in host cells that optimally perform the functions required for their life cycle.

 This effort illustrates the power with which RNA interference and forward genetics can be used to expose the dependencies of human pathogens such as HIV, and in so doing identify potential targets for therapy.

PMID:

18187620

DOI:

10.1126/science.1152725

[Indexed for MEDLINE]

Free full text

Pandeminen HIV-1 virus on saanut oman päivän: 1.12. Miten tämä pandemia alkoi USA: ssa ?

Suomen tilanteesta kertoo HS.fi 

Moni hiv-tartunta todetaan Suomessakin turhan myöhään – Joka neljäs löytyy vasta aids-vaiheessa, vaikka lääkitys voisi estää sen

Hiv yleistyy Euroopassa nopeasti, toisin kuin odotettiin. Lauantaina on kansainvälinen aids-päivä.

Viikon ruotsalainen  lääkärilehti kertoi myös mikä tilanne maailmasas vallitsee HIV- viruksen voittokulun takia.

 HIV on sikäli erikoinen virus , että kissat joilla  sitä virusta  luonnostaan on, eivät näytä siitä sairastuvan. Jos tämä tieto kissoista pitää paikkansa, pitäsi saada selville,  miksi  joku olämminverinen olento voi kantaa  tuolalsita  neurovirusta   ja pysyä hengissä, toistaalta mitä se kissan hengissäpysyminen  ja  taso  sitten käytännössä on, se on taas eri asia. 

lääkärilehti ruotsisas kuvaa  tilanteen kaotisoitunuta  kulkua Amerikassa, jossa  AIDS:n aiheuttamista  40 miljoonasta kuolemantapauksesta on  yli 600 000 tapahtunut USA.ssa.  Lisäksi tätä amerikkalaista statistista numeroa, pidetään liian matalana ja monelle oli kirjoitettu kuolintodistukseen muita syitä joko tietämättömyyden takia  tai   pidetty syynä  traumoja, joita taudin elintapoihin liittyy.  

Kirjoittaja.professori  Jonas F Ludvigsson  oli Ruotsista  käynnillä Columbian yliopsitossa puoli vuotta sitten ja tapasi  ateriapöydässä erään henkilön  joka pöytäkeskustelujen yhteydessä mainitsi olevansa onnellinen siitä, että oli  niinkin kauan pysynyt elossa, vaikka suurin osa hänen tuttavistaan oli  kuollut 1980-luvulla  puhjenneen  aidsepidemian takia New Yorkissa.  Sukeutuneessa keskustelussa  keskustelukumppani  mainitsi olevansa kiitollinen erään lääkärin neuvosta: tri Harold Neu Columbian yliopistosta oli valaissut häntä  aids-taudista että se on infektiotaudin tapainen ja oli suositellut  pitämään vain yhtä  seksuaalipartneria. Hän otti neuvon vastaan ja nyt on sitä mieltä, että tämä on syy,  miksi hän on vielä hengissä  aidsepidemiasta,  vaikka muut ovat  kuolleet.  USA: ssa  aidstautia sairastaneet saivat  yhteiskunnan taholta  hyvin negatiivisen kohtelun ja  jopa useat sairaalatkin N.Y.ssä kieltäytyivät ottamasta vastaan GRID  riskisiä syöpä- ja infektiotapauksia,   joten  aidsiin sairastumista pidettiin  maanpäällisenä helvettinä.   Papit, poliitikot ja sukulaiset  välttivät  aidsiin sairastuneita. 

 Tästä on kirjakin David France:  "How to survive  a plague- the story how activists and scientists tamed  aids" 2017. 1980- luvun alussa iski aids pandemia NewYorkiin. 1981 havaittiin uusi syöpälajikin Kaposin sarkooma, joka  teki kehoon  ihoon ja syviin kudoksiin   sinelmiä-   (lKomemnttini: aivovaikutuksena oli  ylettömän hyperseksuaalinen  käyttäytyminen. syy tai seuraus?).  Opportunistiset infektiot myös puhkesivat kuten alkueläintulehdukset  ja Pneumocystis carinii. Alettiin puhua  elintapatautiin liittyvästä immuunivajeesta. (GRID).  Vuonna 1982 , heinäkuun 1. päivänä CDC rekisteröi  452 aids-tapausta.  Joukossa oli myös suonensisäisiä huumeita käyttäviä.  Sitten löytyi myös kombinaatio hemofilia ja aids  ja monia hemofiliapotilaita, jotka olivat saaneet välttämättömän verensiirtotarpeensa uhrina  viruksen.  Siis virus levisi verivälitteisesti. 

 Ei ollut lääkkeitä, vain elintapaneuvoja, joita ei  otettu vastaan.  Virusta ilemeni  sitten muuallakin kuin New Yorkissa  ja etsittiin leviävän  viruksen lähdettä   "patient zero" ;  yksi sosiopatiatapaus havaittiin useaan kaupunkiin levinneen viruksen  taustalta, mutta tämä ei ollut  purkauksen  "patient -zero". 

Amerikan lehdistössä ilmeni  kirjoitus aids-taudista  vuonna  1983, mutta vasta 1985  heräsi USA:ssa tietoisuus , mitkä elintavat ovat taudin taustalla.  HIV- infektoituneet alkoivat itse  kerätä  varoja  tieteellistä tutkimusta varten, koska  viranomaiset eivät ollet vielä  panostaneet tähän asiaan.

Amerikkalainen Robert Callo ja ranskalainen Luc Montaigner   löysivät  ensimmäisinä  ihmisen  retroviruksen ja osoittivat, että se aiheuttaa tiettyä leukemiamuotoa.  Montaigner havaitsi  varsinaisen hiv- viruksen, mutta  koetti  pitkään  pimittää  tätä ranskalaislöytöä. Vasta kun Nobelkomitea vuonna 2008 antoi Montagnerille - eikä Gallolle -  lääketieteen ja fysiologian Nobel-palkinnon, vaimeni riita siitä kuka hiv-viruksen ensimmäisenä keksi. 

 (Kommenttini : Näin jopa tiede  levitti  pandemiaa tiedemiesten keskinäisten riitojen takia miltei 30 vuotta  ja virus kylväytyi  kaoottisiin  määriin sillä aikaa, pandemiseen tapaan = ihmiskunnassa ei ole vastustuskykyä tälle virukselle). 

Sitten seuraava  hankaluus:  lääketeollisuus ei ollut  kovin innostunut löytämään lääkkeitä aidsia vastaan.  Vaikka  tauti iskikin  vahvasti tiettyyn ihmisjoukkoon,  sairastuneitten lukumäärä koko väestössä USA: ssa oli  sen verran pieni, ettei  ollut oikeutettua   panostaa  asiaan  suuria investointeja.  Ainoa lääkeyhtöä, joka mielellään otti haasteen vastaan oli Burroughs Wellcome. Niinpä  NCI  teki tämän yhtiön kanssa sopimuksen: jos  yhtiö  tunnistaisi molekyylin, joka  saattaisi toimia, NCI ( National Cancer Institute)  suorittaisi kliiniset kokeet ja  lääkkeen jatkokehittelyyn saataisiin verovaroista   rahoitusta. 

Monien kokeilujen jälkeen yhtiö löysui azidotymidiinin- tunnetaan nimellä AZT. Se oli otettu syöpälääkkeenä käyttöön jo vuonna 1964. Tämä oli ratkaiseva  löytö. 

Mutta lääkkeen  korkea hinta teki sen  saatavuuden monille  liian mahdottomaksi ja tästä nousi poliittinen riita.   tuhansia kuoli USA:ssa ilman, että  edes aids- diagnoosia mainittiin edes hallinnon korkeimmalla tasolla. Vasta vuonna 1987 asetettiin aids-komittea  ja sana aids ilmeni  yleiseen tietoisuuteen. Komitea toimitti 576 suositusta, tutkimusta tuettiin ja talouksiin annettiin informaatiota kautta maan. New Yorkissa ehti kuolla 100 000 ihmistä aidsiin. 

----

Kommenttini.  

Maailman lääketieteellisesti  edistynein maa tunnusti aids diagnoosin olemassaolon  vuoden 1987 aikaan. 

Ottaen huomioon eri tasoiset lääketieteelliset kehitysasteet eri maissa,  on ilmeistä että aidskuolemien määrä  ei  parhaimmillaankaan  pystytä  laskemaan.  Se voi olla yli kymmenkertaisesti   nykyinen  diagnosoitu ja kortistoitu aidskuolementapausten lukumäärä.  Tilastot aidsista ovat  miltei kuin jättitsunamien jälkeisten  uhrilukutietojen  koostamista). 

Kommenttini: K un käyn läpi eri geenejä luonnollisen immuunivasteen alalta, siis useita satoja geenejä, huomaan - sivumennen- että miltei joka geeniä on koeteltu HIV-virusten  suhteen, Joten tietoa  HIV-virusluonteesta kertyy  valtavalla vauhdilla.  en ole  vielä  kiinnittänyt niihin tietoihin huomiota seuloessani näitä lähdetietoja. Maintisen tässä niille, joita asia kiinnostaa. 

PubMed haku Gene:  alempana tekstissä on  kerättä tieto kaiksita   geeniä koskevista tutkimuksista.

Ehkä löytyy  vähitellen tehokkaampaa lääkitystä, ehkä rokotusta tai jotain  luonnollista imjmuunivasteta siten   vahvistavaa,  että kehon genomi voi puhdistaa  proviruksen, joka epävakauttaa globaalia genomia.

Ehkä  sekin virus vielä saadaan  asettumaan kuten moni muukin paha virus.

 

 

Rift Valley fever virus (RVFV) ja isäntäkehovaste

https://www.ncbi.nlm.nih.gov/pubmed/26038567/

Proc Natl Acad Sci U S A. 2015 Jun 2;112(22):E2920-9. doi: 10.1073/pnas.1418805112. Epub 2015 May 18.

Virus-induced translational arrest through 4EBP1/2-dependent decay of 5'-TOP mRNAs restricts viral infection.

Hopkins KC¹, Tartell MA¹, Herrmann C¹, Hackett BA¹, Taschuk F¹, Panda D¹, Menghani SV¹, Sabin LR², Cherry S³.

Abstract

The mosquito-transmitted bunyavirus, Rift Valley fever virus (RVFV), is a highly successful pathogen for which there are no vaccines or therapeutics.
Translational arrest is a common antiviral strategy used by hosts.

In response, RVFV inhibits two well-known antiviral pathways that attenuate translation during infection, PKR and type I IFN signaling.

 Despite this, translational arrest occurs during RVFV infection by unknown mechanisms.
 Here, we find that RVFV infection triggers the decay of core translation machinery mRNAs that possess a 5'-terminal oligopyrimidine (5'-TOP) motif in their 5'-UTR, including mRNAs encoding ribosomal proteins, which leads to a decrease in overall ribosomal protein levels.

We find that the RNA decapping enzyme NUDT16 selectively degrades 5'-TOP mRNAs during RVFV infection and this decay is triggered in response to mTOR attenuation via the translational repressor 4EBP1/2 axis.

Translational arrest of 5'-TOPs via 4EBP1/2 restricts RVFV replication, and this increased RNA decay results in the loss of visible RNA granules, including P bodies and stress granules. Because RVFV cap-snatches in RNA granules, the increased level of 5'-TOP mRNAs in this compartment leads to snatching of these targets, which are translationally suppressed during infection.

Therefore, translation of RVFV mRNAs is compromised by multiple mechanisms during infection.

Together, these data present a previously unknown mechanism for translational shutdown in response to viral infection and identify mTOR attenuation as a potential therapeutic avenue against bunyaviral infection.

KEYWORDS:

5′-TOP mRNA; RNA decay; RNA granule; Rift Valley fever virus; translational arrest

PMID:

26038567

PMCID:

PMC4460451

DOI:

10.1073/pnas.1418805112

[Indexed for MEDLINE]

Free PMC Article

hCMV ja APOBECK3A (2017)

 2018,   28.11.
 https://www.spandidos-publications.com/10.3892/mmr.2016.4778

Human cytomegalovirus RL13 protein interacts with host NUDT14 protein affecting viral DNA replication

NUDT14 proteiini on UDPG pyrofosfataasi, joka hydrolysoi UDPG:n tuottaen Glc-1-P ja UMP. 

RL13 on  ihmisen CMV:n myöhäisiä proteiineja ja tekemällä interaktion  NUDT14:n kanssa se  vähentää  NUDT14 proteiinia,  mikä edistää  virus DNA:n kopioita, NUDT14 ylössäätäminen ei kuitenkaan vaikuttanut  virus DNA:n määrään. 

 2017

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686750/

J Virol. 2017 Dec 1; 91(23): e01296-17.

Published online 2017 Nov 14. Prepublished online 2017 Sep 27. doi:  10.1128/JVI.01296-17

PMCID: PMC5686750

PMID: 28956761

APOBEC3A Is Upregulated by Human Cytomegalovirus (HCMV) in the Maternal-Fetal Interface, Acting as an Innate Anti-HCMV Effector

Yiska Weisblum,^a,b,c Esther Oiknine-Djian,^a,b,c Zichria Zakay-Rones,^b Olesya Vorontsov,^a,b,c Ronit Haimov-Kochman,^d Yuval Nevo,^e David Stockheim,^f Simcha Yagel,^d Amos Panet,^b and Dana G. Wolf^a,c

Jae U. Jung, Editor

Jae U. Jung, University of Southern California;

Author information ► Article notes ► Copyright and License information ► Disclaimer

Go to:

ABSTRACT

Human cytomegalovirus (HCMV) is the leading cause of congenital infection and is associated with a wide range of neurodevelopmental disabilities and intrauterine growth restriction. Yet our current understanding of the mechanisms modulating transplacental HCMV transmission is poor. The placenta, given its critical function in protecting the fetus, has evolved effective yet largely uncharacterized innate immune barriers against invading pathogens. Here we show that the intrinsic cellular restriction factor apolipoprotein B editing catalytic subunit-like 3A (APOBEC3A [A3A]) is profoundly upregulated following ex vivo HCMV infection in human decidual tissues—constituting the maternal aspect of the placenta. We directly demonstrated that A3A severely restricted HCMV replication upon controlled overexpression in epithelial cells, acting by a cytidine deamination mechanism to introduce hypermutations into the viral genome. Importantly, we further found that A3 editing of HCMV DNA occurs both ex vivo in HCMV-infected decidual organ cultures and in vivo in amniotic fluid samples obtained during natural congenital infection. Our results reveal a previously unexplored role for A3A as an innate anti-HCMV effector, activated by HCMV infection in the maternal-fetal interface. These findings pave the way to new insights into the potential impact of APOBEC proteins on HCMV pathogenesis.

Aedes egypti-moskiiton neurotranskriptomista

https://www.ncbi.nlm.nih.gov/pubmed/26738925/

BMC Genomics. 2016 Jan 6;17:32. doi: 10.1186/s12864-015-2239-0.

The neurotranscriptome of the Aedes aegypti mosquito.

Matthews BJ¹, McBride CS^2,3, DeGennaro M^4,5, Despo O^6,7, Vosshall LB^8,9.

Abstract
BACKGROUND:
A complete genome sequence and the advent of genome editing open up non-traditional model organisms to mechanistic genetic studies. The mosquito Aedes aegypti is an important vector of infectious diseases such as dengue, chikungunya, and yellow fever and has a large and complex genome, which has slowed annotation efforts. We used comprehensive transcriptomic analysis of adult gene expression to improve the genome annotation and to provide a detailed tissue-specific catalogue of neural gene expression at different adult behavioral states.
RESULTS:
We carried out deep RNA sequencing across all major peripheral male and female sensory tissues, the brain and (female) ovary. Furthermore, we examined gene expression across three important phases of the female reproductive cycle, a remarkable example of behavioral switching in which a female mosquito alternates between obtaining blood-meals from humans and laying eggs. Using genome-guided alignments and de novo transcriptome assembly, our re-annotation includes 572 new putative protein-coding genes and updates to 13.5 and 50.3 % of existing transcripts within coding sequences and untranslated regions, respectively. Using this updated annotation, we detail gene expression in each tissue, identifying large numbers of transcripts regulated by blood-feeding and sexually dimorphic transcripts that may provide clues to the biology of male- and female-specific behaviors, such as mating and blood-feeding, which are areas of intensive study for those interested in vector control. CONCLUSIONS:
This neurotranscriptome forms a strong foundation for the study of genes in the mosquito nervous system and investigation of sensory-driven behaviors and their regulation. Furthermore, understanding the molecular genetic basis of mosquito chemosensory behavior has important implications for vector control.


Yellow fever mosquito:  probable  chitinase: https://www.ncbi.nlm.nih.gov/gene/5576174

Uudenlainen rokote influenssaa vstaan . Väitöskirja 2018 V. Bernasconi

Väitös on edessäpäin Göteborgin Yliopistossa.
Respondentti: Valentina  Bernasconi. Broadly protective nanoparticle-based mucosal vaccine against Influenza virus infection.
Opponentti:  professori Bjarne Bogen, Oslo.

Mistä on kysymys?

Suomennan abstraktia.  Minulla on abstrakti, joka oli tarjolla biomedisiinisessa kirjastossa , kun kävin siellä 12.11. 2018.
Viitettä  nettilinkiin ei näytä  olevan abstraktissa, mutta ilmeisesti otsikolla se on haettavissa. ISBN 978-91-7833-151-2 (Print)
ISBN 978-91-7833-152-9 (PDF).

Suomennan abstraktilehtisestä sisältöä.

" Influenssa on  yksi päätauti  ihmisten virussairauksissa  ja se  kaataa  3- 5 miljoonaa ihmistä vuosittain  vaikean asteiseen  influenssaan  ja noin 250 000- 500 000  menehtyy   sen takia. Pandemisen influenssan  vastainen rokote  on hyvin kysytty ja tehokkain keino   globaalisti leviävien  uusien  esiin puhjenneiden  influenssaviruskantojen  aiheuttamien  tautien riskin  vähentämisessä. Injektiona annettu viruksenvastainen rokote vaatii koulutettua henkilökuntaa ja tiettyä riskiäkin on  kontaminoitujen infektioiden leviämisestä. Sen sijaan  limakalvorokotteet  voitaisiin  tehdä tehokkaammiksi käyttämällä parempia formulointeja ja adjuvantteja.
Tämä tutkijaryhmä on nyt hahmotellut kaksi intranasaalista rokotekandidaattia pandemista flunssaa vastaan perustaen rokoteten kanta-konservoituun M2e peptidiin, joka on  ympätty  CTA1-DD limakalvoadjuvanttiin. Aiemmin on havaittu, että fuusioproteiini CTA1-3M2e-DD stimuloi protektiivista immuniteettia.  Tässä työssä koetettiin edelleen kohentaa sen rokoteominaisuuksia asettamalle se  polysakkaridiin tai liposomipartikkeleihin, joita  annostetaan nenän limakalvolle. Tutkijoiden löydöt viittaavat selvästi siihen, että  tällaiset  kombinoidut  limakalvorokotteet antavat vahvaa pohjaa  tulevien limakalvorokotteiden kehittelyyn. Tässä on kombinoitu vahva CTA1-DD immunomodulaattori ja nanopartikkelit.  Lopuksi väitöskirjatyö antaa  optimistista näkymää mahdollisuudesta kehittää laajasti protektiivinen limakalvorokote influenssaa vastaan  myös nuorille lapsille eikä ainoastaan aikuisille".

Tämä väitöstyö perustuu seuraaville osatöille:

"Porous nanoparticles with self-adjuvanted M2e-fusion protein and recombinant hemagglutinin provide strong and broadly protective immunity against influenza virus infection."
Valentina Bernasconi, Beatrice Bernocchi, Liang Ye, Minh Quan Le, Ajibola Omokanye, Rodolphe Carpentier, Karin Schön, Xavier Saelens, Peter Staeheli, Didier Betbeder, Nils Lycke.
Frontiers in Immunology, 12 September 2018.*
http://doi.org/10.3389/fimmu.2018.02060

Tässä artikkelissa on tätä uutta  tehokasta  rokotetyyppiä kokeiltu hiirille ja freteille . (Ei ihmisille vielä tässä vaiheessa. Työryhmä on hyvin kansainvälinen.

Käsikirjoitusvaiheessa ovat  seuraavat kaksi artikkelia:

A novel combined vaccine consisting of an enzymatically active fusion protein adjuvant and lipid nanoparticles provides broadly protective immunity against influenza infection. Valentina Bernasconi, Karin Norling, Sabina Burazerovic, Karin Schön, Anneli Strömberg, Marta Bally, Fredrik Höök, Nils Lykke.
Manuscript.

targeting follicular dendritic cells with CTA1-DD adjuvant effetively promotes immune responses in neonatala mice and recovery from influenza infection. Sophie Schussek, Valentina Bernasconi, Anneli Strömberg, Karin Schön, Nils Lycke.
Manuscript

Väitöstilaisuus on kuun lopussa.
Yllämainittu * julkaistu  artikkeli antaa laajan taustatieon niille jotka ovat  asiaan ja terminologiaan  perehtyneitä. Saattaa muuten olla hyvä idea. saattaa olla myös paremmin kattava, koska  on helpompi  adminstraatiotapa ja ehkä  laajempi kohdeväestö. Tulee vain mieleen, minkälaisia (hallitsemattomia) ylireaktioita  tehokas  rokote voi herättää immuunvasteesta.  Aika asian selvittää.

Muistiin  19.11. 2018

KAtson myös PubMed hakulaiteella kuinka monta vastausta saa kun hakee sanoilla
intranasal influenzavaccine
Vastauksia
Showing results for intranasal influenza vaccine. Your search for intranasal influenza vaccine retrieved no results.

Kuitenkin freteillä  possuilla tehty intranasaali rokotus löytyi viime kuulta.

• https://www.sciencedirect.com/science/article/pii/S0264410X18313549?via%3Dihub

Vaccine. 2018 Oct 12. pii: S0264-410X(18)31354-9. doi: 10.1016/j.vaccine.2018.10.002. [Epub ahead of print]Immunogenicity and efficacy of the monovalent, trivalent and quadrivalent intranasal live attenuated influenza vaccines containing different pdmH1N1 strains.

Yeolekar LR¹, Ganguly M¹, Tyagi P¹, Ingle NB¹, Stittelaar KJ², Waal L², Scorza FB³, Mahmood K³, Dhere RM⁴

• Int J Nanomedicine. 2018 Oct 24;13:6699-6715. doi: 10.2147/IJN.S178809. eCollection 2018.

Liposomal nanoparticle-based conserved peptide influenza vaccine and monosodium urate crystal adjuvant elicit protective immune response in pigs.
Dhakal S^1,2, Cheng X³, Salcido J³, Renu S^1,2, Bondra K^1,2, Lakshmanappa YS^1,2, Misch C^1,2, Ghimire S^1,2, Feliciano-Ruiz N^1,2, Hogshead B^1,2, Krakowka S⁴, Carson K³, McDonough J³, Lee CW^1,2, Renukaradhya GJ^1,2

• Sivumennen: Löytyi intranasaali rokote verenpaineeseen!
• https://www.ncbi.nlm.nih.gov/pubmed/30328017