A novel gene therapy approach used a membrane-anchored gp41-derived peptide (M87) that includes the T20 sequence, which can protect cells from HIV-1 infection [22]. In an effort to characterize the mechanism of action of the membrane-anchored peptide in comparison to the soluble peptide T20, resistant HIV-1 variants were selected by serial virus passage using cells stably expressing the M87 peptide [23]. Sequence analysis of the resistant variants revealed the HR1 change I48V in combination with the HR2 change N126K, which is the same as the SKY mutation in the T20-dependent variant [1]. This double mutant was confirmed to be resistant to T20 but had a severe reduction in viral fitness in the absence of the T20 peptide.
Nameki et al [24] generated variants resistant to the C34 fusion inhibitor that has a similar mode of action as T20 [7,25]. A resistant variant with the I37K mutation in the GIV motif of HR1 and again the N126K mutation in the SNY motif in HR2 was reported. Binding assays revealed that the I37K mutation in HR1 impaired the binding of the C34 peptide, whereas the N126K mutation enhanced HR2 binding to the mutated HR1.
It is generally accepted that HR1 mutations cause resistance to T20/C34. The combined results indicate that HR2 mutations also play a major role in T20/C34-resistance development. HR2 changes may directly impact on the resistance phenotype, but are more likely to influence viral fitness because uncompensated HR1 mutations slow the fusion kinetics and reduce viral fitness [1,11]. Further studies should investigate the compensatory role of HR2 mutations on Env fusion kinetics and possibly drug-dependence.
Answers to all your Biology Questions
