2nd National Conference Human Retroviruses and Related Infections Washington, DC - January 29 - February 2, 1995

Natl Conf Hum Retrovir Relat Infect 1995 Jan 29-Feb 2;2: (abstract no. 19)

Shaw G¹, Wei X¹, Ghosh S¹, Taylor M¹, Kilby JM JR¹, Johnson V¹, Emini E², Lifson J³, Hahn B¹, Saag M^1
1Univ. of Alabama at Birmingham, AL; ²Merck, Inc., West Point, PA; ³Genelabs, Inc., Redwood City, CA

Although viral replication patterns are certain to contribute importantly to HIV-1 natural history and pathogenesis, remarkably little quantitative information is available, regarding HIV-1 dynamics in humans. In this study, we determined the kinetics of viral clearance from plasma in 17 subjects who initiated treatment with either Nevirapine (NVP) (n=4), the Merck protease inhibitor L-735,524 (n=8), or the Abbott protease inhibitor ABT-538 (n=5). We also determined for NVP-treated subjects the kinetics of virus turnover in uncultured plasma and uncultured PBMCs using automated population sequencing and by in situ expression and drug susceptibility testing of full-length reverse transcriptase (RT) genes.

RESULTS: Repeated determinations of virion-associated RNA in plasma revealed the half-life (t_½)of circulating virus in the 17 subjects to be 2.2 ± 1.1 days (means ± 1 SD). There were no differences in viral t_½ among patient groups. In NVP treated subjects, drug resistance conferring mutations were identified at RT codons 181, 188, and 190. Direct sequencing and in situ RT functional analyses demonstrated complete viral population turnover from wild-type to mutant in the plasma by 14-28 days initiating antiretroviral therapy. Viral population turnover in PBMCs was delayed and less complete.

CONCLUSIONS: The short t_½ of virus in plasma and the rapidity of viral population turnover indicate that ongoing de novo infection of, and virus production by, a relatively short-lived lymphocyte and/or macrophage cell population plays a far greater role in viral pathogenesis than previously recognized. These results, and the methods described here to assess viral population turnover, have broad application in studies of viral pathogenesis, drug resistance, and immune surveillance.

Keywords: HIV Infections, HIV-1, HIV-1 Reverse Transcriptase, Humans, Nevirapine, Ritonavir

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1995-01-29
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