Mutations of Gln64 in the HIV-1 gp41 N-Terminal Heptad Repeat Render Viruses Resistant to Peptide HIV Fusion Inhibitors Targeting the gp41 Pocket

Yu, Xiaoyan; Lu, Lu; Cai, Lifeng; Tong, Pei; Tan, Suiyi; Zou, Peng; Meng, Fanxia; Chen, Yinghua; Jiang, Shibo

doi:10.1128/jvi.05066-11

Cited by 25 publications

(23 citation statements)

References 44 publications

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“…The viral pellet was then resuspended in 100 μl of PBS, before addition of 100 μl MT-2 or TZM-bl cells (1 × 10 5 /ml). After cultur at 37°C for 3 days, p24 production in MT-2 cell culture or luciferase activity in TZM-bl cell culture was tested as previously described [58-60]. …”

Section: Methodsmentioning

confidence: 99%

A bivalent recombinant protein inactivates HIV-1 by targeting the gp41 prehairpin fusion intermediate induced by CD4 D1D2 domains

Pan

et al. 2012

Retrovirology

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BackgroundMost currently approved anti-HIV drugs (e.g., reverse transcriptase inhibitors, protease inhibitors and fusion/entry inhibitors) must act inside or on surface of the target cell to inhibit HIV infection, but none can directly inactivate virions away from cells. Although soluble CD4 (sCD4) can inactivate laboratory-adapted HIV-1 strains, it fails to reduce the viral loads in clinical trials because of its low potency against primary isolates and tendency to enhance HIV-1 infection at low concentration. Thus, it is essential to design a better HIV inactivator with improved potency for developing new anti-HIV therapeutics that can actively attack the virus in the circulation before it attaches to and enter into the target cell.ResultsWe engineered a bivalent HIV-1 inactivator, designated 2DLT, by linking the D1D2 domain of CD4 to T1144, the next generation HIV fusion inhibitor, with a 35-mer linker. The D1D2 domain in this soluble 2DLT protein could bind to the CD4-binding site and induce the formation of the gp41 prehairpin fusion-intermediate (PFI), but showed no sCD4-mediated enhancement of HIV-1 infection. The T1144 domain in 2DLT then bound to the exposed PFI, resulting in rapid inactivation of HIV-1 virions in the absence of the target cell. Beside, 2DLT could also inhibit fusion of the virus with the target cell if the virion escapes the first attack of 2DLT.ConclusionThis bivalent molecule can serve as a dual barrier against HIV infection by first inactivating HIV-1 virions away from cells and then blocking HIV-1 entry on the target cell surface, indicating its potential for development as a new class of anti-HIV drug.

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Section: Methodsmentioning

confidence: 99%

A bivalent recombinant protein inactivates HIV-1 by targeting the gp41 prehairpin fusion intermediate induced by CD4 D1D2 domains

Pan

et al. 2012

Retrovirology

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“…89,90 Approaches that also use initial cellular entry restriction have therefore become very interesting to the HIV-1 gene therapy community. Although overexpression of peptides that block virus fusion via interaction with the gp41 pocket has been proposed, 91,92 mutational escape can occur as well 93,94 and the immunogenicity of gp41-derived peptides remains to be tested. Restriction factors such as TRIM5a are thought to play important roles in protecting against nonhost retroviruses and limiting cross-species transmission.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Assessment of Mutant Human TRIM5α as an Anti-HIV-1 Transgene

et al. 2015

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“…S1 in the supplemental material). K63N is located adjacent to Q64, which was previously shown to be a resistance-associated substitution (32). The synonymous change in V72 (GTG to GTA) may influence the RRE structural stability, as we have previously described (28).…”

Section: E Nfuvirtide (T-20)mentioning

confidence: 99%

HIV-1 Resistance Mechanism to an Electrostatically Constrained Peptide Fusion Inhibitor That Is Active against T-20-Resistant Strains

Shimane¹,

Kawaji²,

Miyamoto³

et al. 2013

Antimicrob Agents Chemother

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e T-20EK is a novel fusion inhibitor designed to have enhanced ␣-helicity over T-20 (enfuvirtide) through engineered electrostatic interactions between glutamic acid (E) and lysine (K) substitutions. T-20EK efficiently suppresses wild-type and T-20-resistant variants. Here, we selected T-20EK-resistant variants. A combination of L33S and N43K substitutions in gp41 were required for high resistance to T-20EK. While these substitutions also caused resistance to T-20, they did not cause cross-resistance to other known fusion inhibitors.

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Mutations of Gln64 in the HIV-1 gp41 N-Terminal Heptad Repeat Render Viruses Resistant to Peptide HIV Fusion Inhibitors Targeting the gp41 Pocket

Cited by 25 publications

References 44 publications

A bivalent recombinant protein inactivates HIV-1 by targeting the gp41 prehairpin fusion intermediate induced by CD4 D1D2 domains

A bivalent recombinant protein inactivates HIV-1 by targeting the gp41 prehairpin fusion intermediate induced by CD4 D1D2 domains

Preclinical Assessment of Mutant Human TRIM5α as an Anti-HIV-1 Transgene

HIV-1 Resistance Mechanism to an Electrostatically Constrained Peptide Fusion Inhibitor That Is Active against T-20-Resistant Strains

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