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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

On the basis of previous studies of dicistronic (dc) polioviruses that carried two internal ribosomal entry sites (L. Alexander, H.-H. Lu, and E. Wimmer, Proc. Natl. Acad. Sci. USA 91:1406-1410, 1994; A. Molla, S. K. Jang, A. V. Paul, Q. Reuer, and E. Wimmer, Nature [London] 356:255-257, 1992), we have constructed a variety of dc polioviruses which express foreign genetic elements that were inserted either between two internal ribosomal entry site elements upstream of the poliovirus open reading frame (pPNENPO derivatives) or upstream of the open reading frame for the poliovirus proteinase 2Apro (pDI-E2A derivatives). Surprisingly, the addition of an N-terminal secretory pathway signal sequence to the open reading frame of the inserted foreign sequences (specifying either truncated versions of human immunodeficiency virus type 1 [HIV-1] gp120 or chloramphenicol acetyltransferase) resulted in a null phenotype, whereas removal of the signal sequence led to the production of viable viruses. Constructs that carried a foreign gene with a signal sequence were negative in RNA synthesis, an observation that suggested a very early block in viral replication. The insertion of transmembrane sequences downstream of the leader sequence did not reverse the replication block. Studies of dc polioviruses that encoded the truncated versions of HIV-1 gp120 showed an increase in genetic stability that correlated with a decrease in the size of the insert. A dc construct that contained a minigene encoding the principal neutralization determinant of HIV-1 produced a stable virus that retained the foreign sequence through multiple passages in cultured cells. These data indicate that dc polioviruses have potential as vaccines for the expression of small foreign epitopes.
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PMID:Construction and genetic analysis of dicistronic polioviruses containing open reading frames for epitopes of human immunodeficiency virus type 1 gp120. 754 43

Several animal viruses inhibit host protein synthesis, but only some members of the picornavirus group are known to do so by cleaving translation initiation factor eIF4G. Here we report that infection of human CD4(+) cells with HIV-1 also leads to proteolysis of eIF4G and profound inhibition of cellular translation. Purified HIV-1 protease directly cleaves eIF4GI at positions 678, 681, and 1086, separating the three domains of this initiation factor. Proteolysis of eIF4GI by HIV-1 protease, as with poliovirus 2A protease, inhibits protein synthesis directed by capped mRNAs but allows internal ribosome entry site-driven translation. These findings indicate that HIV-1, a member of retrovirus group, shares with picornaviruses the capacity to proteolyze eIF4G.
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PMID:HIV-1 protease cleaves eukaryotic initiation factor 4G and inhibits cap-dependent translation. 1160 67

The human immunodeficiency virus protease (HIV-1 PR) was expressed both in the yeast Saccharomyces cerevisiae and in mammalian cells. Inducible expression of HIV-1 PR arrested yeast growth, which was followed by cell lysis. The lytic phenotype included loss of plasma membrane integrity and cell wall breakage leading to the release of cell content to the medium. Given that neither poliovirus 2A protease nor 2BC protein, both being highly toxic for S. cerevisiae, were able to produce similar effects, it seems that this lytic phenotype is specific of HIV-1 PR. Drastic alterations in membrane permeability preceded the lysis in yeast expressing HIV-1 PR. Cell killing and lysis provoked by HIV-1 PR were also observed in mammalian cells. Thus, COS7 cells expressing the protease showed increased plasma membrane permeability and underwent lysis by necrosis with no signs of apoptosis. Strikingly, the morphological alterations induced by HIV-1 PR in yeast and mammalian cells were similar in many aspects. To our knowledge, this is the first report of a viral protein with such an activity. These findings contribute to the present knowledge on HIV-1-induced cytopathogenesis.
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PMID:Cell killing by HIV-1 protease. 1237 Jan 91

Nonsense-mediated mRNA decay (NMD) in mammalian cells targets cap-binding protein 80 (CBP80)-bound mRNA during or after a pioneer round of translation. It is unknown whether eukaryotic translation initiation factor 4G (eIF4G) functions in the pioneer round. We show that baculovirus-produced CBP80 and CBP20 independently interact with eIF4GI. The interactions between eIF4G and the heterodimer CBP80/20 suggest that eIF4G has a function in the pioneer initiation complex rather than merely a presence during remodeling to the steady-state complex. First, NMD is inhibited upon eIF4G cleavage by HIV-2 or poliovirus 2A protease. Second, eIF4GI coimmunopurifies with pre-mRNA, indicating that it associates with transcripts before the pioneer round. Third, eIF4G immunopurifies with Upf NMD factors and eIF4AIII, which are constituents of the pioneer translation initiation complex. We propose a model in which eIF4G serves to connect CBP80/20 with other initiation factors during the pioneer round of translation.
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PMID:eIF4G is required for the pioneer round of translation in mammalian cells. 1536 57

The infection of baby hamster kidney (BHK) cells by Sindbis virus gives rise to a drastic inhibition of cellular translation, while under these conditions the synthesis of viral structural proteins directed by the subgenomic 26S mRNA takes place efficiently. Here, the requirement for intact initiation factor eIF4G for the translation of this subgenomic mRNA has been examined. To this end, SV replicons that contain the protease of human immunodeficiency virus type 1 (HIV-1) or the poliovirus 2A(pro) replacing the sequences of SV glycoproteins have been constructed. BHK cells electroporated with the different RNAs synthesize protein C and the corresponding protease at late times. Notably, the proteolysis of eIF4G by both proteases has little effect on the translation of the 26S mRNA. In addition, recombinant viable SVs were engineered that encode HIV-1 PR or poliovirus 2A protease under the control of a duplicated late promoter. Viral protein synthesis at late times of infection by the recombinant viruses is slightly affected in BHK cells that contain proteolysed eIF4G. The translatability of SV genomic 49S mRNA was assayed in BHK cells infected with a recombinant virus that synthesizes luciferase and transfected with a replicon that expresses poliovirus 2Apro. Under conditions where eIF4G has been hydrolysed significantly the translation of genomic SV RNA was deeply inhibited. These findings indicate a different requirement for intact eIF4G in the translation of genomic and subgenomic SV mRNAs. Finally, the translation of the reporter gene that encodes green fluorescent protein, placed under the control of a second duplicate late promoter, is also resistant to the cleavage of eIF4G. In conclusion, despite the presence of a cap structure in the 5' end of the subgenomic SV mRNA, intact eIF4G is not necessary for its translation.
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PMID:Translation of Sindbis virus 26S mRNA does not require intact eukariotic initiation factor 4G. 1634 28

Gene therapy is a promising strategy for the treatment of HIV infection, but cell specificity remains an issue. Recently we have developed a new concept for a drug or gene delivery system responding to cellular signals (D-RECS) to achieve cell-specific transgene expression using a non-viral polymer-based vehicle. According to this concept, intracellular signaling enzymes, which are activated specifically in target cells, are used to trigger transgene expression. We previously applied this concept to HIV-1 protease and showed that the recombinant protease could act as a suitable signal. Here we further developed this system to achieve highly specific transgene expression in HIV-infected cells. We prepared a polymeric gene regulator grafted with a cationic peptide containing the HIV-Tat peptide via a specific substrate for HIV-1 protease. The regulator formed a stable polyplex with the transgene, suppressing its transcription. HIV-1 protease cleaved the peptide and released the transgene, which was consequently expressed specifically in activated HIV-infected cells, but remained unreleased and inactive in uninfected cells. The validity of this approach was further confirmed by applying it to the CVB1 2A protease of coxsackievirus (Picornaviridae family). This strategy should be widely applicable for specific expression of a variety of therapeutic genes in virus-infected cells.
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PMID:Specific transgene expression in HIV-infected cells using protease-cleavable transcription regulator. 1973 2

The 30 different species of mRNAs synthesized during the HIV-1 replication cycle are all capped and polyadenilated. Internal ribosome entry sites have been recognized in the 5' untranslated region of some mRNA species of HIV-1, which would contribute to an alternative mechanism of initiation of mRNA translation. However, the Cap-dependent translation is assumed to be the main mechanism driving the initiation of HIV-1 protein synthesis. In this work, we describe a cell system in which lower to higher levels of transient expression of the poliovirus 2A protease strongly inhibited cellular Cap-dependent translation with no toxic effect to the cells during a 72-hour time frame. In this system, the synthesis of HIV-1 proteins was inhibited in a temporal dose-dependent way. Higher levels of 2A protease expression severely inhibited HIV-1 protein synthesis during the first 24 hours of infection consequently inhibiting viral production and infectivity. Intermediate to lower levels of 2A Protease expression caused the inhibition of viral protein synthesis only during the first 48 hours of viral replication. After this period both protein synthesis and viral release were recovered to the control levels. However, the infectivity of viral progeny was still partially inhibited. These results indicate that two mechanisms of mRNA translation initiation contribute to the synthesis of HIV-1 proteins; during the first 24-48 hours of viral replication HIV-1 protein synthesis is strongly dependent on Cap-initiation, while at later time points IRES-driven translation initiation is sufficient to produce high amounts of viral particles.
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PMID:HIV-1 transcripts use IRES-initiation under conditions where Cap-dependent translation is restricted by poliovirus 2A protease. 2452 Apr 5

Herein we describe the construction of recombinant human rhinoviruses (rHRVs) encoding HIV Gag or Tat by inserting the full length tat gene or regions of the gag gene flanked by sequences encoding the HRV 2A protease cleavage site into the junction between HRV genes encoding structural (P1) and non-structural (P2) proteins. Most recombinants were unstable, but this was corrected by mutation of the flanking cleavage sites. Thereafter, all rHRV constructs retained the inserts throughout six passages. Such constructs may find utility as vaccine vectors to generate mucosal immunity.
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PMID:Engineering human rhinovirus serotype-A1 as a vaccine vector. 2586 80