Grant RM, Liegler T, Elkin C, Nijjar S, Wrin T, Hoh R, Kolberg J, Hellerstein M, Hellmann NS, Petropoulos CJ, Deeks SG; Conference on Retroviruses and Opportunistic Infections.
Program Abstr 8th Conf Retrovir Oppor Infect Conf Retrovir Oppor Infect 8th 2001 Chic Ill. 2001 Feb 4-8; 8: 276 (abstract no. LB4).
Gladstone Inst, Univ of California, San Francisco.
Background: Recombinant viruses with decreased protease inhibitor (PI)-susceptibility often display decreased replication capacity in vitro. However, in vivo measures of the fitness of PI resistant viruses have not been reported. Methods: As previously described, subjects experiencing long-term virological failure (HIV RNA > 2500 copies/mL) on a PI-based regimen were found to have PI- resistant strains (MT) that were overgrown by drug susceptible virus populations (WT) during a structured treatment interruption (STI). The rate of WT overgrowth was assessed by measuring the WT: MT ratio in the plasma at weekly timepoints during the STI using a validated quantitative differential probe hybridization assay (Bayer Diagnostics), which interrogates the PR and RT coding sequences at 16 loci. The in vivo fitness difference (selection coefficient) between WT and MT virus for each subject was calculated using a standard equation: S=1/t*ln(PoQt/PtQo). Corresponding in vitro viral replication capacities were assessed using an adaptation of the PhenoSense HIV drug susceptibility assay (ViroLogic). Results: In vivo fitness differences between WT and MT viruses in 12 subjects ranged from 3.3 to 36.1 (median 13.9) and correlated with increases in viral load during STI (rho=0.62, P=0.03). WT: MT ratios extrapolated to the time prior to stopping therapy varied between 1: 60 to 1: 65,000 and correlated negatively with WT: MT fitness difference (rho=-0.86, P=0.0003). Differences in the in vitro replication capacity of viruses sampled at baseline and after WT overgrowth correlated well with in vivo fitness measures (rho=0.82, P=0.001) and the increase in viral load during STI (rho=0.80, P=0.002). Conclusions: Using direct measures of in vivo fitness, we observed that PI-resistant HIV-1 is markedly less fit than PI susceptible virus. This may account for persistent partial viral suppression observed with PI-resistant viremia. During effective therapy, WT virus appears to persist, albeit at very low levels. Viral fitness measured in vivo compared well with an in vitro replication capacity assay, indicating that rapid recombinant virus assays may provide virologically relevant information.
Publication Types:
Keywords:
- Acquired Immunodeficiency Syndrome
- Anti-HIV Agents
- HIV
- HIV Infections
- HIV Protease
- HIV Protease Inhibitors
- HIV Seropositivity
- HIV-1
- Hemagglutination Tests
- In Vitro
- Protease Inhibitors
- Viral Load
- reverse transcriptase, Human immunodeficiency virus 1
Other ID:
UI: 102244550
From Meeting Abstracts