Viral dynamics and in vivo fitness of HIV-1 in the presence and absence of enfuvirtide.
OBJECTIVE
To estimate the in vivo fitness cost of enfuvirtide (ENF) resistance, we analyzed dynamic shifts in the HIV-1 quasispecies under changing selective pressure in 3 subjects on failing ENF-based regimens who interrupted ENF while maintaining stable background regimens. Subsequently, ENF was readministered for 4 weeks as "pulse intensification."


METHODS
The proportion of plasma virus carrying the V38A mutation in gp41 was quantified by allele-specific real-time polymerase chain reaction in serial samples collected from 3 subjects at 1- to 4-week intervals. Fitness differences were calculated using a method that corrected for time dependence of the viral replication rate.


RESULTS
The V38A mutant made up >or=85% of the quasispecies at baseline and decayed to <5% over 12-24 weeks; plasma HIV-1 RNA levels remained stable during this time. Fitness differences for mutant versus wild type ranged from -25% to -65%, providing in vivo evidence for the reduced fitness of ENF-resistant HIV-1. The V38A mutant virus reemerged rapidly during the ENF pulse.


CONCLUSIONS
These results demonstrate that the HIV-1 quasispecies undergoes dynamic changes in response to withdrawal and reinitiation of fusion inhibitor therapy. The relative stability of plasma HIV-1 titers during decay of V38A suggests that factors other than viral fitness likely define viral load set-point in patients with advanced disease.
Marconi
Vincent
V
Section of Retroviral Therapeutics, Brigham and Women's Hospital and Division of AIDS, Harvard Medical School, Boston, MA 02139, USA.
Bonhoeffer
Sebastian
S
Paredes
Roger
R
Lu
Jing
J
Hoh
Rebecca
R
Martin
Jeffery N
JN
Deeks
Steven G
SG
Kuritzkes
Daniel R
DR
D024882:Drug Resistance, Viral; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000097:blood / Q000235:genetics* / Q000627:therapeutic use; D023581:HIV Fusion Inhibitors / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D009154:Mutation; D010446:Peptide Fragments / Q000627:therapeutic use*; D019562:Viral Load
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D000077560:Enfuvirtide