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onsdag 5 december 2018

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

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Email authorView ORCID ID profile and
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^Deceased
Retrovirology201714:36
Received: 15 May 2017
Accepted: 30 May 2017
Published:
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

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 (-).
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.
An external file that holds a picture, illustration, etc.
Object name is ijpr-15-595-g001.jpg 
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 (-).
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.


HIV-1 retroviral replication cycle (derived from 22).
 PMC full text:
2015 Apr 23;10(4):e0123935. doi: 10.1371/journal.pone.0123935. eCollection 2015.

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

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

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

Sirtuin-1 and HIV-1: an overview.

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. 

måndag 3 december 2018

Luonnollinen imuunivaste ja HIV-1 . Artikkeleita.

Löytöjä 3.12. 2018

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

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

lördag 1 december 2018

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.

 


 





torsdag 29 november 2018

Rift Valley fever virus (RVFV) ja isäntäkehovaste

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

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

onsdag 28 november 2018

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

Jae U. Jung, Editor
Jae U. Jung, University of Southern California;
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.