Specific mutations in HIV-1 gp41 are associated with immunological success in HIV-1-infected patients receiving enfuvirtide treatment

Stefano Aquaro, Roberta D'Arrigo, Valentina Svicher, Giovanni Di Perri, Sergio Lo Caputo, Ubaldo Visco-Comandini, Mario Santoro, Ada Bertoli, Francesco Mazzotta, Stefano Bonora, Valerio Tozzi, Rita Bellagamba, Mauro Zaccarelli, Pasquale Narciso, Andrea Antinori, Carlo Federico Perno

Research output: Contribution to journalArticle

Abstract

Objectives: 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 log10/mL (P=0.0002) and a CD4 increase from 48 to 106 cells/mm3 (P=0.008). While viraemia rebounded to 4.8 and 4.6 log10/mL at week 12 and 36, respectively, CD4 continued to increase to 136 cells/ mm3 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.

Original languageEnglish
Pages (from-to)714-722
Number of pages9
JournalJournal of Antimicrobial Chemotherapy
Volume58
Issue number4
DOIs
Publication statusPublished - Oct 15 2006

Keywords

  • CD4 cell counts
  • Glycosylation
  • Resistance
  • Viraemia

ASJC Scopus subject areas

  • Pharmacology
  • Microbiology

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