[18] NEW MUTATIONS AT RESIDUE POSITIONS CRITICAL FOR T-20 RESISTANCE IN T-20-NAIVE PATIENTS INFECTED WITH CLADE

XI International HIV Drug Resistance Workshop: Basic Principles and Clinical Implications

Seville, Spain, 2–5 July 2002

NEW MUTATIONS AT RESIDUE POSITIONS CRITICAL FOR T-20 RESISTANCE IN T-20-NAÏVE PATIENTS INFECTED WITH CLADE B HIV-1 ISOLATES

Antivir Ther. 2002;7(Suppl 1):S14 (abstract no. 18)

F Roman¹, D Gonzalez², R Boulme², C Lambert¹, S Deroo¹, A Fischer¹, T Baurith¹, T Staub¹, V Arendt¹, F Schneider¹, R Hemmer¹ and JC Schmit¹
¹Retrovirology Laboratory, CRP-Santé, Luxembourg; and ²Advanced Biological Laboratories, Biomedical Information Unit, Luxembourg

BACKGROUND: T-20 is a lead compound of the new class of antiretroviral drugs called fusion inhibitors. Resistance-associated mutations to T-20 located in the heptad repeat 1 (HR-1) domain of gp41 have been described in vitro or in clinical trials: G36S, V38M, V38A, Q39H, Q40H, N43D and other combinations of the tripeptide motif involving residues 36, 37 and 38. We determined the prevalence of these mutations in B and non-B HIV-1 viruses of T-20-naïve individuals at the beginning of their follow-up in the Luxembourg HIV cohort. For B isolates, we also studied the polymorphism of the HR-1 domain in the course of HIV-1 infection.

METHODS: Plasma samples of patients infected with B (n=48) and non-B (n=48) isolates were collected at the beginning of their follow-up in the cohort. After RNA extraction, 550 bp fragments from gp41 were amplified by RT-PCR and directly sequenced on an automated ABIPrism 3100. Available sequences were aligned with HXB2 and screened for amino acid changes at positions 36 to 40 and 43. A similar analysis was performed for all B isolates, after an average duration of infection of 5.8 years (range, 3–8.9 years).

RESULTS: Sequences were obtained for 43 non-B isolates and 42 B isolates at the beginning of the follow-up, and for 42 B isolates at the time of the second analysis. None of the non-B sequences had amino acid substitutions at the T-20 resistance-related residues. In contrast, three B isolates (6.2%) exhibited substitutions at residues 37 or 39. A Q39R mutation was present in two isolates before initiation of antiretroviral treatment and at the time of the second analysis. An I37V mutation appeared in another isolate after 4.8 years of HIV-1 infection and 3.6 years of antiretroviral treatment.

CONCLUSION: No classical resistance-associated mutations to T-20 were identified in B or non-B isolates in our study. However, we identified two new mutations in B isolates in a region critical for T-20 activity: I37V and Q39R. The impact of these mutations on T-20 sensitivity has not been determined in vitro. These findings emphasize the need to develop phenotypic resistance testing for fusion inhibitors.

PRESENTING AUTHOR: F Roman

Download PDF of this abstract.

2002-07-02
18

Copyright © 2002 - International Medical Press Ltd. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the International Medical Press Ltd. 2-4 Idol Lane, London EC3R 5DD UK.