Title The role of integrase in HIV-1 maturation
Title (english) Uloga integraze u sazrijevanju HIV-1
Author Noa Čemeljić
Mentor Igor Jurak (mentor)
Committee member Ivana Ratkaj (predsjednik povjerenstva)
Committee member Željka Maglica (član povjerenstva)
Committee member Igor Jurak (član povjerenstva)
Granter University of Rijeka (Faculty of Biotechnology and Drug Development) Rijeka
Defense date and country 2019-06-26, Croatia
Scientific / art field, discipline and subdiscipline BIOTECHNICAL SCIENCES Biotechnology
Abstract Integrase (IN) is one of the most important enzymes in the replication of the HIV-1 virus, as it integrates viral DNA (vDNA) into the genome of the host cells. However, recent studies have suggested a new surprising role of IN in HIV-1 maturation. If IN is inhibited either by mutations or by allosteric integrase inhibitors (ALLINIs), viral ribonucleoprotein complexes (vRNPs) are often eccentrically localized outside of the capsid (CA). Such viral particles are non-infectious and are blocked at an early stage of the reverse transcription in the target cells, as a result of premature degradation of IN and viral RNA (vRNA) genome, together with the spatial separation of reverse transcriptase (RT) from vRNA.
IN directly binds the vRNA genome in virions by its surface exposed lysine residues, exhibiting a distinct preference for selected vRNA structural elements. In this way, IN provides nucleation points by bridging separate RNA molecules, promoting the effective compaction of vRNPs. These interactions then ensure the proper packaging of vRNPs inside the CA.
Even though the mechanism of action of ALLINIs, an emerging class of anti-HIV drugs, is still not fully understood, it seems that they mostly act by blocking the IN-vRNA interaction, which results in aberrant non-infectious particles.
This non-catalytic role of IN enables the understanding of the HIV-1 maturation process in greater detail, which can be successfully used in the development of new drugs, such as ALLINIs. However, a lot of research still needs to be done, as there is a lot of detail in this IN-driven maturation process that still needs to be explained.
Abstract (croatian) Integraza (IN) je jedan od najvažnijih enzima u replikaciji HIV-1 virusa, budući da integrira virusnu DNA (vDNA) u genom stanice domaćina. Međutim, novije studije su predložile novu, iznenađujuću ulogu IN u sazrijevanju HIV-1. Ukoliko je IN inhibirana bilo mutacijama bilo alosteričkim inhibitorima integraze (ALLINI-ji), virusni ribonukleoproteinski kompleksi (vRNP-ovi) su često acentrično lokalizirani izvan kapside (CA). Ove čestice nisu infektivne i blokirane su u ranoj fazi reverzne transkripcije u ciljnim stanicama, kao rezultat preuranjene degradacije IN i virusnog RNA (vRNA) genoma, zajedno s prostornom odvojenošću reverzne transkriptaze (RT) od vRNA.
IN izravno veže vRNA u virionima putem svojih površinski izloženih lizinskih ostataka, pokazujući izrazite preference za određene vRNA strukturne elemente. Na ovaj način IN stvara nukleacijske točke, premošćujući odvojene RNA molekule i unaprjeđujući učinkovito zbijanje RNP-ova. Ove interakcije osiguravaju ispravno pakiranje vRNP-ova unutar
CA.
Iako mehanizam djelovanja ALLINI-ja, skupine anti-HIV lijekova u nastajanju, još uvijek nije do kraja razjašnjen, čini se da oni većinski djeluju blokirajući IN-vRNA interakcije, što rezultira abnormalnim neinfektivnim česticama.
Ova nekatalitička uloga IN omogućava detaljnije shvaćanje procesa sazrijevanja HIV-1, što se može uspješno upotrijebiti u razvoju novih lijekova poput ALLINI-ja. Međutim, potrebno je provesti još mnogo istraživanja jer puno detalja u ovom IN potpomognutom procesu sazrijevanja još uvijek mora biti razjašnjeno.
Keywords
HIV-1
integrase
maturation
vRNPs
vRNA packaging
IN-vRNA interactions
ALLINIs
Keywords (croatian)
HIV-1
integraza
sazrijevanje
vRNP-ovi
pakiranje vRNA
IN- vRNA interakcije
ALLINI-ji
Language english
URN:NBN urn:nbn:hr:193:920638
Study programme Title: Biotechnology and drug research Study programme type: university Study level: undergraduate Academic / professional title: sveučilišni/a prvostupnik/prvostupnica biotehnologije i istraživanja lijekova (sveučilišni/a prvostupnik/prvostupnica biotehnologije i istraživanja lijekova)
Type of resource Text
File origin Born digital
Access conditions Open access
Terms of use
Repository Repository of the University of Rijeka, Faculty of Biotechnology and Drug Development
Created on 2019-07-02 15:51:49