Evolution of genotypic resistance to enfuvirtide in HIV-1 isolates from different group M subtypes

Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology (Impact Factor: 3.02). 03/2009; 44(4):325-8. DOI: 10.1016/j.jcv.2009.01.012
Source: PubMed


Enfuvirtide is active against isolates from different HIV-1 subtypes. In vitro and in vivo studies reveal that resistance mutations are primarily found within the region spanning amino acid 36-45 of gp41. However, most studies include only subtype B strains, while it is known that especially the env region is very divergent among subtypes.
To analyze the gp41 HR1 genetic evolution during failure of enfuvirtide-containing salvage regimens in 19 HIV-1 patients infected with strains from different group M subtypes.
The gp41 sequence was determined at baseline and upon failure in 19 patients. For a subset of 7 patients, samples were available after discontinuation of enfuvirtide.
Our results confirmed the conserved nature of the HR1 region. Escape mutants during chronic treatment with enfuvirtide were mainly observed within region 36-45. One novel mutation was identified, i.e. S42G in a subtype A1 strain.
Different subtypes escape enfuvirtide selective pressure through similar mutational patterns, however a new S42G variant was observed. The in vivo selection of S42G suggests that it might play a role in enfuvirtide resistance. Therefore, it could be considered as a candidate mutation to be included within drug resistance interpretation systems.

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    • "proven for the rare T69-ins and Q151M reverse transcriptase mutations against nucleoside reverse transcriptase inhibitors. We therefore wanted to investigate the phenotypic impact of the S42G, N43T and A50V gp41 mutations selected in non-B subtypes under pressure of enfuvirtide (Covens et al., 2009b). Such investigations could provide additional information on the residual activity of enfuvirtide when recycling would be considered and are important for understanding the mechanism of action of enfuvirtide and the next-generation fusion inhibitor sifuvirtide. "
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