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Antimicrobial Agents and Chemotherapy, July 2009, p. 2816-2823, Vol. 53, No. 7
0066-4804/09/$08.00+0 doi:10.1128/AAC.01067-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Treatment with the Fusion Inhibitor Enfuvirtide Influences the Appearance of Mutations in the Human Immunodeficiency Virus Type 1 Regulatory Protein Rev
Valentina Svicher,1*,
Claudia Alteri,1,
Roberta D'Arrigo,2
Alessandro Laganà,3
Maria Trignetti,1
Sergio Lo Caputo,4
Anna Paola Callegaro,5
Franco Maggiolo,5
Francesco Mazzotta,4
Alfredo Ferro,3
Salvatore Dimonte,1
Stefano Aquaro,6
Giovanni di Perri,7
Stefano Bonora,7
Chiara Tommasi,2
Maria Paola Trotta,2
Pasquale Narciso,2
Andrea Antinori,2,
Carlo Federico Perno,1,2, and
Francesca Ceccherini-Silberstein1,2
University of Rome Tor Vergata,1 National Institute of Infectious Diseases (INMI) L. Spallanzani, Rome, Italy,2 University of Catania, Catania, Italy,3 Clinic of Infectious Diseases, Hospital Santa Maria Annunziata, Florence, Italy,4 Department of Infectious Diseases, Ospedali Riuniti, Bergamo, Italy,5 Department of Pharmaco-Biology, University of Calabria, Rende (CS), Italy,6 Clinic of Infectious Diseases, University of Turin, Hospital Amedeo di Savoia, Turin, Italy7
Received 7 August 2008/ Returned for modification 2 October 2008/ Accepted 24 December 2008
The gp41-encoding sequence of the env gene contains in two separate regions the Rev-responsive elements (RRE) and the alternative open reading frame of the second exon of the regulatory protein Rev. The binding of Rev to the RRE allows the transport of unspliced/singly spliced viral mRNAs out of the nucleus, an essential step in the life cycle of human immunodeficiency virus type 1 (HIV-1). In this study, we have investigated whether the fusion-inhibitor enfuvirtide (ENF) can induce mutations in Rev and if these mutations correlate with the classical ENF resistance gp41 mutations and with viremia and CD4 cell count. Specific Rev mutations were positively associated with ENF treatment and significantly correlated with classical ENF resistance gp41 mutations. In particular, a cluster was observed for the Rev mutations E57A (E57Arev) and N86Srev with the ENF resistance gp41 mutations Q40H (Q40Hgp41) and L45Mgp41. In addition, the presence at week 48 of the E57Arev correlates with a significant viremia increase from baseline to week 48 and with a CD4 cell count loss from baseline to week 48. By modeling the RRE structure, we found that the Q40gp41 and L45gp41 codons form complementary base pairs in a region of the RRE involved in Rev binding. The conformation of this Rev-binding site is disrupted when Q40Hgp41 and L45Mgp41 occur alone while it is restored when both mutations are present. In conclusion, our study shows that ENF pressure may also affect both Rev and RRE structures and can provide an excellent example of compensatory evolution. This highlights the multiple roles of ENF (and perhaps other entry inhibitors) in modulating the correct interplay between the different HIV-1 genes and proteins during the HIV-1 life cycle.
* Corresponding author. Mailing address: Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. Phone: 39 06 72596551. Fax: 39 06 72596039. E-mail: valentina.svicher{at}uniroma2.it
Published ahead of print on 5 January 2009.
V.S. and C.A. contributed equally to the work.
For the INMI-Collaborative Group for Clinical Use of HIV Genotype Resistance Test.
Antimicrobial Agents and Chemotherapy, July 2009, p. 2816-2823, Vol. 53, No. 7
0066-4804/09/$08.00+0 doi:10.1128/AAC.01067-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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