Natural variability in the HR-1 and HR-2 domains of HIV type 1 gp41 from different clades circulating in Italy

The human immunodeficiency virus type 1 (HIV-1) HR-1 and HR-2 gp41 regions were sequenced in a total of 228 plasma or peripheral blood mononuclear cell samples obtained from an equal number of enfuvirtide-naive subjects for pol genotypic resistance testing in clinical practice. Phylogenetic analysis of the env sequences indicated that 102 belonged to subtype B and 95 to non-B subtypes (31 CRF02_AG, 21 F1, 14 C, 11 A1/A2/A3, 9 CRF01_AE, 9 others) while the remaining 31 were unique recombinant forms. There was considerable variability in the consensus sequence of different clades, particularly in HR-2. The HR-1 amino acid region 36-45, containing all of the enfuvirtide resistance mutations so far characterized, was well conserved except for position 42 where serine and asparagine were unevenly distributed in different subtypes. Enfuvirtide resistance mutations were not present in any sample, reinforcing the expectation that enfuvirtide is effective against many different HIV-1 clades and recombinants. However, some of the mutations outside the amino acid 36-45 region and provisionally suggested to play a role in modulating resistance were detected in a minority of cases. Molecular epidemiological surveys coupled with long-term observation of in vivo response to enfuvirtide and future fusion inhibitors are required to clarify the clinical significance of gp41 natural variability.