Background:  We investigated gp41-variability and correlation with viro-immunological parameters in 52 HIV-1-infected patients receiving enfuvirtide (T-20) added as a single active drug to a backbone of a failing regimen

Methods:  We analyzed 210 sequences of entire HIV-1 gp41 and clinical follow-up from 52 T-20-treated patients at baseline and monthly for 48 weeks. The association of mutations with viremia viral load and CD4 count was assessed by Mann-Whitney test

Results:  The addition of T-20 to the failing ART regimen induced at 4 weeks a significant decrease of viral load from 5.1 log (stable in the last 12 weeks prior to T-20) to 4.3 log (p = 0.0002), and a significant increase of CD4 from 48 copies/mL (continuously decreasing in the last 12weeks prior T-20) to 106 copies/mL (p = 0.008). While viral load rapidly rebounded to 4.7 and 5 log at 12-48 weeks, respectively, CD4 increased to 129 copies/mL at 48weeks. T-20-resistance mutations were absent at baseline, but occurred almost invariably in a short period after treatment. V38A/E/M, Q39H, or N42D/T appeared (usually alone) within 48 weeks, each at 25 to 40% frequency; also N43D and G36D/S occurred alone, at 15% frequency. Q40H, L44M, L45M were less common (each with ~10% frequency at 32 weeks), but often appeared in association. The viro-immunological outcome of T-20-treated patients remarkably varied according to gp41-mutations occurring during T-20 treatment. V38A/E (present in 38.5% of patients) was associated with an increase of CD4 from BL (48 copies/mL) of 4.1-fold (142 copies/mL) at 24weeks and 5.8 (196 cells/mL) at 36 weeks (p = 0.004 and 0.02 compared without V38A/E, respectively). V38A/E did not correlate with significant changes in viral load (from 4.9 log at baseline to 4.4 t0 4.8 at 24 to 36 weeks, p = ns). By contrast, Q40H+L45M co-presence (occurring in 10.6% of patients) is associated with CD4 loss from 71 copies/mL at baseline to 26 copies/mL at 36 weeks (p = 0.02), without significant changes in viral load (from 5 log at baseline to 5 log at 36 weeks). Mutation N126K (observed in 5 patients, but never found at baseline) abrogates the fourth gp41-glycosylation site and correlates with a 1.7-fold increase in CD4 at 24weeks.

Conclusions:  Conformational changes induced by V38A/E in the key, highly conserved GIV motif of gp41-HR1, is tightly related with a loss of HIV-induced damage of immune system. This facilitates CD4 recovery through mechanisms that can be virus- or immune-mediated (i.e., loss of fusion efficiency upon cell targets, or exposure of new epitopes), which is not applicable to protease or reverse transcriptase inhibitors, and thus important for design of innovative therapeutic strategies