Specific mutations in HIV-1 gp41 are associated with immunological success in HIV-1-infected patients receiving enfuvirtide treatment.
OBJECTIVE
To investigate gp41 variability and correlation with viro-immunological parameters in 54 HIV-1-infected patients receiving enfuvirtide added as single active drug to a failing regimen.


METHODS
One hundred and two HIV-1 gp41 sequences and clinical follow-up from 54 enfuvirtide-treated patients were analysed from baseline to week 36 of treatment. The association of mutations with viraemia/CD4 count was assessed by Mann-Whitney test.


RESULTS
The addition of enfuvirtide to the failing regimen induced at week 4 a viraemia decrease from 5.1 to 4.3 log(10)/mL (P = 0.0002) and a CD4 increase from 48 to 106 cells/mm(3) (P = 0.008). While viraemia rebounded to 4.8 and 4.6 log(10)/mL at week 12 and 36, respectively, CD4 continued to increase to 136 cells/mm(3) at week 36. Enfuvirtide resistance mutations, rarely found at baseline, occurred in 45/54 (83.3%) enfuvirtide-treated patients. V38A/E were the most represented mutations at all time-points. The presence of V38A/E was significantly associated with a 4.5-fold CD4 increase from baseline to week 24 and with a 6-fold increase at week 36 (P = 0.004 and 0.02 compared without V38A/E, respectively), without significant correlation with viraemia. In contrast, Q40H + L45M (present in six enfuvirtide-treated patients at week 36) correlated with CD4 loss from baseline to week 36 (P = 0.02), without significant correlation with viraemia. Mutation N126K (observed in six enfuvirtide-treated patients, never found at baseline) abrogates the fourth gp41 glycosylation site and correlates with a 2.1-fold CD4 increase at week 24.


CONCLUSIONS
Specific enfuvirtide resistance mutations (V38A/E) are associated with a sustained CD4 increase, without remarkable effects upon viraemia. This CD4 recovery, due to virus- and immune-mediated mechanisms most probably not applicable to protease/reverse transcriptase inhibitors, is important for innovative therapeutic strategies.
Aquaro
Stefano
S
Department of Experimental Medicine and Biochemical Sciences, University of Rome, Tor Vergata, Rome, Italy. aquaro@uniroma2.it
D'Arrigo
Roberta
R
Svicher
Valentina
V
Perri
Giovanni Di
GD
Caputo
Sergio Lo
SL
Visco-Comandini
Ubaldo
U
Santoro
Mario
M
Bertoli
Ada
A
Mazzotta
Francesco
F
Bonora
Stefano
S
Tozzi
Valerio
V
Bellagamba
Rita
R
Zaccarelli
Mauro
M
Narciso
Pasquale
P
Antinori
Andrea
A
Perno
Carlo Federico
CF
D000328:Adult; D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral / Q000235:genetics; D000077560:Enfuvirtide; D005260:Female; D006031:Glycosylation; D015700:HIV Envelope Protein gp41 / Q000235:genetics* / Q000627:therapeutic use; D023581:HIV Fusion Inhibitors / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010446:Peptide Fragments / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D014766:Viremia / Q000188:drug therapy / Q000821:virology
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D000077560:Enfuvirtide