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Antimicrobial Agents and Chemotherapy, September 2004, p. 3253-3259, Vol. 48, No. 9
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.9.3253-3259.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Genotype and Phenotype Patterns of Human Immunodeficiency Virus Type 1 Resistance to Enfuvirtide during Long-Term Treatment

Stefano Menzo,1 Antonella Castagna,2 Alessia Monachetti,1 Hamid Hasson,2 Anna Danise,2 Elisabetta Carini,2 Patrizia Bagnarelli,1 Adriano Lazzarin,2,3 and Massimo Clementi3,4*

Istituto di Microbiologia e Scienze Biomediche, Università Politecnica delle Marche, Ancona,1 Divisione di Malattie Infettive, I.R.C.C.S. Istituto Scientifico San Raffaele,2 Università Vita-Salute San Raffaele,3 Laboratorio di Microbiologia, Diagnostica & Ricerca San Raffaele, Milan, Italy4

Received 3 December 2003/ Returned for modification 5 February 2004/ Accepted 24 May 2004

The human immunodeficiency virus type 1 (HIV-1) fusion inhibitor enfuvirtide has recently been introduced into clinical practice and has exhibited efficient anti-HIV-1 activity in combination with other antiretroviral agents. In the present study, we addressed the effect of long-term treatment with enfuvirtide on the intrahost evolution of HIV-1. The genotype and phenotype patterns and the relative replication capacity (rRC) of enfuvirtide-resistant HIV-1 mutants were evaluated in samples from 11 subjects (7 virological nonresponders and 4 responders) who received the compound for more than 1 year in combination with different regimens. Selection of one or more mutations clustering in a sequence (amino acids 36 to 45) of the gp41 N-terminal heptad repeat was observed in samples from the seven virological nonresponders but not in those from responders. In two subjects who discontinued enfuvirtide, reversion of the resistant genotype was detected within 3 months. Recombinant clones bearing mutated gp41 sequences displayed reduced susceptibilities to enfuvirtide, with the 50% inhibitory concentrations (IC50s) ranging from 0.6 to 12.8 µg/ml, whereas the IC50 for isolates with baseline sequences was 0.013 ± 0.010 µg/ml. Interestingly, long-term monitoring of resistant variants provided evidence that ongoing adaptation to the drug is paralleled by phenotypic changes. A limited drop in the rRC in the absence of drug was observed for clones from four of the seven nonresponders bearing mutations associated with resistance. Overall, the data indicate that the different genotype patterns associated with a detectable degree of HIV-1 resistance to enfuvirtide generated during long-term treatments are characterized by a substantially low genetic barrier, possible ongoing adaptation with increased degrees of resistance, and limited influence on the viral rRC.

* Corresponding author. Mailing address: Università Vita-Salute San Raffaele, Laboratorio di Microbiologia, Ospedale San Raffaele, via Olgettina 60, I-20132 Milan, Italy. Phone: 39 022643.2649. Fax: 39 022643.2640. E-mail: massimo.clementi{at}hsr.it.

Antimicrobial Agents and Chemotherapy, September 2004, p. 3253-3259, Vol. 48, No. 9
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.9.3253-3259.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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