HIV-1 Vif-Derived Peptide Inhibits Drug-Resistant HIV Proteases

Blumenzweig, Immanuel; Baraz, Lea; Friedler, Assaf; Danielson, U. Helena; Gilon, Chaim; Kotler, Moshe

doi:10.1006/bbrc.2002.6732

Cited by 7 publications

(5 citation statements)

References 53 publications

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“…Our results also contradict recent in vitro studies that have suggested the converse notion, namely, that Vif inhibits PR action (2,5,23,40,52). Although these investigations have shown that Vif-derived peptides may inhibit PR in the context of HIV-1 infection and interfere with HIV-1 replication, demonstration of premature or excessive proteolysis of Gag during ⌬vif HIV-1 infection is awaited.…”

Section: Discussioncontrasting

confidence: 98%

Comprehensive Investigation of the Molecular Defect in vif -Deficient Human Immunodeficiency Virus Type 1 Virions

Gaddis

Chertova

Sheehy

et al. 2003

J Virol

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Replication of human immunodeficiency virus type 1 (HIV-1) in primary blood lymphocytes, certain T-cell lines (nonpermissive cells), and most likely in vivo is highly dependent on the virally encoded Vif protein.Evidence suggests that Vif acts late in the viral life cycle during assembly, budding, and/or maturation to counteract the antiviral activity of the CEM15 protein and possibly other antiviral factors. Because HIV-1 virions produced in the absence of Vif are severely restricted at a postentry, preintegration step of infection, it is presumed that such virions differ from wild-type virions in some way. In the present study, we established a protocol for producing large quantities of vif-deficient HIV-1 (HIV-1/⌬vif) from an acute infection of nonpermissive T cells and performed a thorough examination of the defect in these virions. Aside from the expected lack of Vif, we observed no apparent abnormalities in the packaging, modification, processing, or function of proteins in ⌬vif virions. In addition, we found no consistent defect in the ability of ⌬vif virions to perform intravirion reverse transcription under a variety of assay conditions, suggesting that the reverse transcription complexes in these particles can behave normally under cell-free conditions. Consistent with this finding, neither the placement of the primer tRNA 3 Lys nor its ability to promote reverse transcription in an in vitro assay was affected by a lack of Vif. Based on the inability of this comprehensive analysis to uncover molecular defects in ⌬vif virions, we speculate that such defects are likely to be subtle and/or rare.

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Section: Discussioncontrasting

confidence: 98%

Comprehensive Investigation of the Molecular Defect in vif -Deficient Human Immunodeficiency Virus Type 1 Virions

Gaddis

Chertova

Sheehy

et al. 2003

J Virol

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“…To verify the analysis method shown in Scheme , we applied it to analyze the translation processes of wild‐type HIV‐1 in the absence and in the presence of PI, and in parallel we have analyzed the translation processes of RNA extracted from the G48 V mutated virus, which is resistant to saquinavir 35. 36 Figure 4 shows the Faradaic impedance spectra corresponding to the final step of precipitation of 2 on the electrode supports after the application of the analytical protocol outlined in Scheme . Figure 4 A shows the spectra (curves a and b) obtained for the translation of the RNA derived from the wild‐type virus in the absence of the inhibitor according to paths B1 and B2 in Scheme , respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Culture medium containing the virus was clarified from cell debris by centrifugation at 10 000 rpm for 10 min and the clear supernatant was centrifuged for 45 min at 45 000 rpm in a Beckman centrifuge (SW 50.1 rotor). The drug‐resistant HIV‐1 (NL4‐3) strain that includes the G48 V mutated PR was constructed and propagated as described previously 36…”

Section: Methodsmentioning

confidence: 99%

Electronic Transduction of HIV‐1 Drug Resistance in AIDS Patients

Alfonta

Blumenzweig²,

Zayats

et al. 2004

ChemBioChem

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A drug composition consisting of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) is commonly used in AIDS therapy. A major difficulty encountered with the therapeutic composite involves the emergence of drug-resistant viruses, especially to the PIs, regarded as the most effective drugs in the composition. We present a novel bioelectronic means to detect the appearance of mutated HIV-1 exhibiting drug resistance to the PI saquinavir. The method is based on the translation of viral RNA, the association of cleaved or uncleaved Gag polyproteins at an electrode surface functionalized with the respective antibodies, and the bioelectronic detection of the Gag polyproteins associated with the surface. The bioelectronic process includes the association of anti-MA or anti-CA antibodies, the secondary binding of an antibody-horseradish peroxidase (HRP) conjugate, and the biocatalyzed precipitation of an insoluble product on the electronic transducers. Faradaic impedance measurements and quartz crystal microbalance analyses are employed to follow the autoprocessing of the Gag polyproteins. The method was applied to determine drug resistance in infected cultured cells and also in blood samples of consenting AIDS patients. The method described here is also applicable to the determination of drug effectiveness in AIDS patients and to screening of the efficiency of newly developed drugs.

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“…Thus, our results suggest that Vif interferes with the dimerization of PR (Babe et al , 1991 , 1992 ; Schramm et al , 1996 , 1999 ). This suggestion is further supported by the following findings: (i) Vif88–98 specifically inhibits PR as a non-substrate-based inhibitor (Friedler et al , 1999 ); (ii) HIV-1 Vif-derived peptide Vif88–98 inhibits HIV-2 PR but not ASLV PR and pepsin (Blumenzweig et al , 2002 ; Friedler et al , 1999 ). These results are compatible with the sequence similarity between the PR termini of HIV-1 and HIV-2 ( 1 PQITL 5 … 95 CTLNF 99 and 1 PQFSL 5 … 95 MSLNL 99 , respectively).…”

Section: Full Textmentioning

confidence: 86%