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The HIV-1 integrase-LEDGF allosteric inhibitor MUT-A: resistance profile, impairment of virus maturation and infectivity but without influence on RNA packaging or virus immunoreactivity

Overview of attention for article published in Retrovirology, November 2017
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2 tweeters

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Title
The HIV-1 integrase-LEDGF allosteric inhibitor MUT-A: resistance profile, impairment of virus maturation and infectivity but without influence on RNA packaging or virus immunoreactivity
Published in
Retrovirology, November 2017
DOI 10.1186/s12977-017-0373-2
Pubmed ID
Authors

Céline Amadori, Yme Ubeles van der Velden, Damien Bonnard, Igor Orlov, Nikki van Bel, Erwann Le Rouzic, Laia Miralles, Julie Brias, Francis Chevreuil, Daniele Spehner, Sophie Chasset, Benoit Ledoussal, Luzia Mayr, François Moreau, Felipe García, José Gatell, Alessia Zamborlini, Stéphane Emiliani, Marc Ruff, Bruno P. Klaholz, Christiane Moog, Ben Berkhout, Montserrat Plana, Richard Benarous

Abstract

HIV-1 Integrase (IN) interacts with the cellular co-factor LEDGF/p75 and tethers the HIV preintegration complex to the host genome enabling integration. Recently a new class of IN inhibitors was described, the IN-LEDGF allosteric inhibitors (INLAIs). Designed to interfere with the IN-LEDGF interaction during integration, the major impact of these inhibitors was surprisingly found on virus maturation, causing a reverse transcription defect in target cells. Here we describe the MUT-A compound as a genuine INLAI with an original chemical structure based on a new type of scaffold, a thiophene ring. MUT-A has all characteristics of INLAI compounds such as inhibition of IN-LEDGF/p75 interaction, IN multimerization, dual antiretroviral (ARV) activities, normal packaging of genomic viral RNA and complete Gag protein maturation. MUT-A has more potent ARV activity compared to other INLAIs previously reported, but similar profile of resistance mutations and absence of ARV activity on SIV. HIV-1 virions produced in the presence of MUT-A were non-infectious with the formation of eccentric condensates outside of the core. In studying the immunoreactivity of these non-infectious virions, we found that inactivated HIV-1 particles were captured by anti-HIV-specific neutralizing and non-neutralizing antibodies (b12, 2G12, PGT121, 4D4, 10-1074, 10E8, VRC01) with efficiencies comparable to non-treated virus. Autologous CD4(+) T lymphocyte proliferation and cytokine induction by monocyte-derived dendritic cells (MDDC) pulsed either with MUT-A-inactivated HIV or non-treated HIV were also comparable. Although strongly defective in infectivity, HIV-1 virions produced in the presence of the MUT-A INLAI have a normal protein and genomic RNA content as well as B and T cell immunoreactivities comparable to non-treated HIV-1. These inactivated viruses might form an attractive new approach in vaccine research in an attempt to study if this new type of immunogen could elicit an immune response against HIV-1 in animal models.

Twitter Demographics

The data shown below were collected from the profiles of 2 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 23 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 23 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 3 13%
Researcher 3 13%
Student > Master 3 13%
Student > Bachelor 2 9%
Professor 1 4%
Other 3 13%
Unknown 8 35%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 4 17%
Medicine and Dentistry 4 17%
Immunology and Microbiology 3 13%
Agricultural and Biological Sciences 2 9%
Chemistry 2 9%
Other 0 0%
Unknown 8 35%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 15 November 2017.
All research outputs
#7,589,287
of 12,145,106 outputs
Outputs from Retrovirology
#423
of 598 outputs
Outputs of similar age
#160,685
of 285,171 outputs
Outputs of similar age from Retrovirology
#10
of 14 outputs
Altmetric has tracked 12,145,106 research outputs across all sources so far. This one is in the 23rd percentile – i.e., 23% of other outputs scored the same or lower than it.
So far Altmetric has tracked 598 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 6.0. This one is in the 18th percentile – i.e., 18% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 285,171 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 34th percentile – i.e., 34% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 14 others from the same source and published within six weeks on either side of this one. This one is in the 14th percentile – i.e., 14% of its contemporaries scored the same or lower than it.