[13] Novel mutations in a highly conserved region of HIV-1 gp41 are associated with T-20 treatment

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

Seville, Spain, 2–5 July 2002

NOVEL MUTATIONS IN A HIGHLY CONSERVED REGION OF HIV-1 GP41 ARE ASSOCIATED WITH T-20 TREATMENT

Antivir Ther. 2002;7(Suppl 1):S11 (abstract no. 13)

SD Kemp¹, L Ruiz², AM Lucas¹, A Bonjoch², J Martinez-Picado², BA Larder¹ and B Clotet²
¹Visible Genetics, Cambridge, UK, ²IrsiCaixa Foundation, Hospital Germans Trias i Pujol, Barcelona, Spain

BACKGROUND: T-20 is a peptide mimetic of the HR2 region of HIV-1 gp41 currently in phase III clinical development as an HIV-1 fusion inhibitor. Unlike other HIV inhibitors it targets HIV-1 early in its life cycle and is, therefore, expected to have activity against HIV-1 strains that are highly resistant to inhibitors of protease or reverse transcriptase. Mutations in gp41 in the region of amino acids 36–45 have been identified from both in vitro and in vivo studies as being associated with decreased sensitivity to T-20, and the importance of these mutations has been confirmed by site directed mutagenesis. This study was designed to identify genetic determinants of T-20 resistance in a patient cohort treated for 24 weeks.

METHODS: Eighteen plasma samples from a randomised, multicentre, open label controlled clinical trial, representing baseline (BL) and week 24 samples from nine patients from a single centre, were analysed by population based sequencing of gp41. The subjects were HIV-infected patients, on antiretroviral therapy (ART) with viral load >5000 copies/ml, who were either triple class experienced or harboured HIV-1 with resistance mutations to all three current drug classes. RT-PCR and sequencing primers were optimised for the amplification and sequencing of HIV-1 envelope for group M viruses.

RESULTS: In addition to T-20, patients typically received tenofovir, lopinavir/ritonavir, plus other antiretrovirals. Viral load responses at week 24 were mixed with a number of subjects having incomplete viral suppression. In one such subject no changes in the conserved amino acid residues in the gp41 HR1 region were observed. However, isolates from two additional subjects who also showed incomplete viral suppression revealed genetic differences in the HR1 region between amino acid codons 30 to 45. Mutations detected in one patient sample were Q40H and L45M both of which are in residues that are highly conserved across HIV-1 group M subtypes. Mutations detected in the other patient sample were A30T, S35A and N43S. The first two of these changes have been previously described as polymorphisms, however codon 43 is highly conserved across HIV-1 group M subtypes.

CONCLUSION: This study identified both novel mutations and those that have been previously identified as either associated or not associated with decreased sensitivity to T-20. These mutations occurred in a highly conserved region of HIV-1 gp41 isolated from patients treated with T-20. Further research is required to establish the precise role of these mutations in T-20 susceptibility and treatment response.

PRESENTING AUTHOR: SD Kemp

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2002-07-02
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