Objectives: 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 ≥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.
From the *Section of Retroviral Therapeutics, Brigham and Women's Hospital and Division of AIDS, Harvard Medical School, Boston, MA; †Theoretical Biology, ETH Zentrum, Zurich, Switzerland; and ‡Department of Medicine; §Epidemiology and Biostatistics, University of California, San Francisco, and San Francisco General Hospital, San Francisco, CA. Vincent Marconi is now with the HIV Unit, Wilford Hall United States Air Force Medical Center, 2200 Bergquist Drive, Suite 1, Lackland AFB, TX 78236.
Received for publication March 5, 2008; accepted March 6, 2008.
Presented in part at the 1st International Workshop on HIV Entry Inhibition, December, 2005, Bethesda, MD [abstract 10], and at the 13th Conference on Retroviruses and Opportunistic Infections, February 5-8, 2006, Denver, CO [abstract M-188].
Correspondence to: Dr Daniel R. Kuritzkes, MD, Section of Retroviral Therapeutics, Brigham and Women's Hospital, 65 Landsdowne Street, Room 449, Cambridge, MA 02139 (e-mail: firstname.lastname@example.org).