Long-term monitoring of genotypic and phenotypic resistance to T20 in treated patients infected with HIV-1.
The aim of this study was to investigate the susceptibility to T20 and the dynamics of amino acid changes in HR1 and HR2 of gp41 of HIV-1 obtained from plasma, peripheral blood mononuclear cells (PBMC), and primary isolates (PI) in four highly antiretroviral-experienced patients. These patients received T20 plus an antiretroviral regimen and were followed-up over a period of 40-72 weeks. In one non-responder patient, N43D substitution was detected at 12 weeks of treatment, in association with a value of T20-IC50 of 10 microg/ml (10-fold increase). Double mutations N42T + N43D were observed in plasma RNA at 32 weeks and remained detectable up to 16 weeks after the withdrawal of the drug. The S138A substitution in HR2 was observed in plasma RNA at 32 weeks, and both in plasma RNA and in PI DNA at 40 weeks, associated with an increase of the T20-IC50 to 25 microg/ml (25-fold increase). Mutations V101G and E137K, not reported previously, were also observed in the HR2 region. Whether these new substitutions play a role in T20 resistance needs to be examined. In three temporary responders, coinciding with viral load rebound, G36D, and N42T substitutions were observed at 12, 24, and 40 weeks. G36D mutation was associated with a value of T20-IC50 of 5 microg/ml. The HR2 S138A mutation was detected after the detection of HR1 substitutions and was associated with an increase in the level of T20-IC50 to 125 microg/ml (125-fold increase) All these data reinforce the role of gp41 amino acids 36-45 and the potential influence of the HR2 S138A mutation in the genotypic/phenotypic resistance to T20.
Pérez-Alvarez
L
L
Area de Patogenia Viral, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
Carmona
R
R
Ocampo
A
A
Asorey
A
A
Miralles
C
C
Pérez de Castro
S
S
Pinilla
M
M
Contreras
G
G
Taboada
J A
JA
Nájera
R
R
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D004279:DNA, Viral / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000008:administration & dosage / Q000235:genetics* / Q000627:therapeutic use; D023581:HIV Fusion Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000008:administration & dosage / Q000627:therapeutic use*; D011533:Proviruses / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D016879:Salvage Therapy; D016415:Sequence Alignment; D016896:Treatment Outcome
D019380:Anti-HIV Agents; D004279:DNA, Viral; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D012367:RNA, Viral; D000077560:Enfuvirtide