Evolution of genotypic and phenotypic resistance to Enfuvirtide in HIV-infected patients experiencing prolonged virologic failure.
Four heavily antiretroviral-experienced HIV-infected patients had significant plasma HIV-RNA reductions (>1 log) after beginning an Enfuvirtide (ENF)-based rescue regimen. However, all had viral rebound shortly thereafter, sustaining high levels of plasma viremia over 80 weeks. These patients developed rapidly genotypic and phenotypic resistance to ENF. Mutations within the HR1 env region were selected (N43D in three and G36V/D in one), resulting in high-level phenotypic resistance to ENF. Interestingly, two patients had a sustained CD4+ T-cell increase and two maintained stable CD4+ T-cell counts despite virologic failure under ENF. The possible mechanisms involved in this response were examined. Changes in virus tropism from R5 to R5/X4 were observed in two patients, in parallel with increases in ENF phenotypic resistance. Low levels of T-cell activation, T-cell turnover, and cytotoxic T lymphocyte (CTL) activity were found in all four patients. An overall increase in the proportion of viruses released from cells of the macrophage lineage was observed. In summary, single mutations at the HR1 env region result in significant loss of susceptibility to ENF. Despite virologic failure, these patients may maintain elevated CD4+ counts through a reduction in their overall immune activation.
Poveda
Eva
E
Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain.
Rodés
Berta
B
Labernardière
Jean-Louis
JL
Benito
José Miguel
JM
Toro
Carlos
C
González-Lahoz
Juan
J
Faudon
Jean-Louis
JL
Clavel
François
F
Schapiro
Jonathan
J
Soriano
Vincent
V
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral / Q000235:genetics; D000077560:Enfuvirtide; D015684:Gene Products, pol / Q000502:physiology; D005814:Genes, Viral; D015752:Genes, env; D015751:Genes, pol; D006678:HIV / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use*; D023581:HIV Fusion Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D006801:Humans; D008213:Lymphocyte Activation; D008264:Macrophages / Q000821:virology; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D019713:Receptors, CCR5 / Q000502:physiology; D019718:Receptors, CXCR4 / Q000502:physiology; D016879:Salvage Therapy; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014766:Viremia
D015684:Gene Products, pol; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D012367:RNA, Viral; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D000077560:Enfuvirtide