Author(s): Hanna SL, Yang C, Owen SM, Lal RB, Hanna SL, Yang C, Owen SM, Lal RB
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Abstract BACKGROUND: Two of the fusion inhibitors T-20 and 5-helix polypeptide have been shown to be potent inhibitors of cell-to-cell fusion and are currently under investigation as therapy for HIV-1. OBJECTIVES: To examine variability of HIV-1 gp41 heptads repeat regions (HR1 and HR2), with special emphasis on the presence of T-20 resistance mutations and 5-helix variability at critical epitopes, in treatment-naive patients infected with diverse HIV-1 subtypes from different geographic regions. METHODS: A total of 150 specimens representing HIV-1 group M subtypes (A-G) from persons naive to HIV-1 viral entry inhibitor therapy were used to amplify and sequence a 506 bp segment of transmembrane protein. RESULTS: In general, both HR1 (a.a. 540-593) and HR2 (a.a. 628-673) domains were highly conserved. Sequence analysis of the T-20 resistant domain (a.a. 547-549, GIV) revealed that 99\% of the specimens (149 of 150) carried a T-20 sensitive genotype. The critical epitopes involved in the 5-helix interaction include residues at positions 628W, 631W, 635I, 638Y, 642I, 645L, 649S, 652Q, 656N, and 659E. Analysis of the 150 specimens revealed that all had identical residues at six of these positions, whereas two positions had minor variations (635 and 649) and two (645 and 659) appeared to have subtype-specific substitutions. CONCLUSIONS: This data indicates that there is limited resistance to T-20 in these worldwide populations and that the critical epitopes for effective 5-helix binding are highly conserved across all subtypes. Taken together, these data suggest that T-20 and 5-helix should provide useful additives to current antiretroviral therapy for clinical management of HIV disease.
This article was published in AIDS
and referenced in Journal of AIDS & Clinical Research