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Ce, though the C-terminal domains (CTDs) form dimers that connect adjacent
HIV-1 preintegration complexes PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/26437915 (PICs) isolated from the cytoplasm several hours soon after virus entry contain only low levels of CA protein, suggesting that viral uncoating occurs within the cytoplasm before nuclear entry [12,13]. Reverse transcription complexes have been isolated at earlier time points, with some of these complexes retaining low levels of CA [14]. Recent studies employing imaging and ARQ 531 inhibitor pharmacologic approaches have recommended that uncoating requires spot inside a handful of hours following cell entry, and could possibly be linked to reverse transcription [15,16]. Within a prior study, we observed that mutations in CA that lead to altering the intrinsic stability from the HIV-1 capsid are related with impaired infectivity [17]. These capsid stability mutants were competent for viral particle assembly and release and exhibited typical core morphology by electron microscopy, but most exhibited defects in reverse transcription in target cells. One of many mutants, Q63A/Q67A, resulting in unstable capsids in vitro, was competent for reverse transcription but impaired for nuclear import [17,18]. Interestingly, PICs recovered from this mutant contained elevated levels of CA and have been impaired for integration in vitro. Collectively, these research recommend that uncoating happens progressively inside the cytoplasm and is required for productive reverse transcription, nuclear import, and integration.Viral determinants in addition to CA could also be involved in HIV-1 uncoating. A triple-stranded viral DNA structure designed through reverse transcription was implicated in uncoating at the nuclear pore. This so-called "DNA flap" structure was shown to be required for nuclear import, but not reverse transcription [19]. Mutations within the HIV-1 matrix protein (MA) also can lead to early postentry defects, suggesting that MA also regulates uncoating [20-22]. HIV-1 uncoating may well also be modulated by host cell factors. Cellular proteins that might affect uncoating incorporate cyclophilin A and restrictive alleles of TRIM5a [23,24]. Even so, no matter whether these proteins play a direct function in uncoating remains unknown, owing to a lack of sensitive and validated cell-based assays to study HIV-1 uncoating in target cells along with the difficulty in distinguishing functional from nonfunctional particles [25]. A recent study also reported that lysates from activated CD4 + lymphocytes, but not quiescent CD4 + lymphocytes, induce disassembly of isolated HIV-1 PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/27107493 cores in vitro, suggesting that HIV-1 uncoating might differ in activated vs. resting T cells [26]. Amino acids recognized to influence HIV-1 capsid stability are situated on both domains in the CA protein in varying locat.Ce, even though the C-terminal domains (CTDs) form dimers that connect adjacent hexamers via a CTD-CTD interface [1-5]. The existence of an NTD-CTD interface in the retroviral capsid was originally inferred from research of your Rous sarcoma virus (RSV), in which two lethal MHR mutations inside the CTD have been rescued by compensatory mutations inside the NTD [6]. In HIV-1, NTD-CTD contacts had been detected by hydrogen-deuterium exchange [7] and chemical cross-linking [8], and in structures of CA hexamers and pentamers [9,10]. Following cell entry, the HIV-1 particle releases its core in to the host cytoplasm. Subsequently, the core undergoes an uncoating approach, which we define as disassembly or dissociation from the viral capsid from the internal RNP complex [11].
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