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


Seville, Spain, 2–5 July 2002


MINIMAL VARIATION IN THE T-20 BINDING DOMAIN OF DIFFERENT HIV-1 SUBTYPES FROM ANTIRETROVIRAL-NAÏVE AND -EXPERIENCED PATIENTS

Antivir Ther. 2002;7(Suppl 1):S13 (abstract no. 16)

Li Xu, S Hue, D Ratcliffe, J Workman, S Jackson, P Cane and D Pillay
PHLS Antiviral Susceptibility Reference Unit, University of Birmingham, UK

BACKGROUND: In vitro serial passage experiments identify two mutations, namely G36S and V38M, in a glycine-isoleucine-valine (GIV) motif within the amino HR1 region of gp41, which are associated with reduced susceptibility to T-20, and these mutations also emerge in vivo. The bulk of studies on the biological basis of drug susceptibility have been undertaken on subtype B viruses. However, the most prevalent viruses worldwide are non-B subtype, and the prevalence of non-B viruses is increasing in Europe. Currently there is lack of information on primary resistance of HIV-1 to T-20 in different subtypes. Therefore the sequences of HR1 region of gp41 from T-20 treatment-naïve patients infected with subtype B and non-B HIV-1 strains were analysed for the presence of naturally occurring primary mutations linked to resistance to T-20.

METHODS: Plasma samples from 57 T-20 naïve patients were studied. These individuals included reverse transcriptase inhibitor and protease inhibitor-experienced and -naïve individuals, and were infected with a range of HIV-1 subtypes. A 272 base pair region covering the gp41 coding sequence from amino acid 1 to amino acid 70 was amplified by nested RT-PCR and sequenced using Beckman CEQ2000 protocols. Subtype was designated on the basis of pol sequence.

RESULTS: HIV-1 subtypes tested included A (n=15), B (12), C (14), D (7), G (4) and AE or AG (5). No primary mutations associated with resistance to T-20 (G36S and V38M) were observed in any the samples examined. Of the 57 samples, 17 had a silent mutation at the third position of amino acid 36 (GGT-GGC), mainly in subtype A (12/15), G (2/4) and AE/AG (2/5) viruses. No other consistent patterns of changes within the area of genome sequenced were observed. These viruses included those with a range of reverse transcritpase and protease drug resistance-associated mutations, the presence of which did not appear to influence the gp41 sequences.

CONCLUSION: This is the first report on sequence analysis of the HR-1 domain of different subtypes of HIV-1 in T-20-naïve patients. Despite the genetic variability among subtypes, our data suggests that the 'GIV' motif within the HR1 region is highly conserved, and natural variants may only rarely occur in the absence of specific selective pressure.

PRESENTING AUTHOR: D Pillay

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2002-07-02
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