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Journal of Virology, December 2003, p. 13146-13155, Vol. 77, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.24.13146-13155.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Fitness Is a Determining Factor in Viral Rebound and Set Point in Chronic Infection

Alexandra Trkola,1* Herbert Kuster,1 Christine Leemann,1 Claudia Ruprecht,1,{dagger} Beda Joos,1 Amalio Telenti,2 Bernhard Hirschel,3 Rainer Weber,1 Sebastian Bonhoeffer,4 Huldrych F. Günthard,1 and the Swiss HIV Cohort Study{ddagger}

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, 8091 Zurich,1 Division of Infectious Diseases, University Hospital Lausanne, 1011 Lausanne,2 Division of Infectious Diseases, University Hospital Geneva, 1211 Geneva,3 Institute for Ecology, ETH Zentrum Zurich, 8092 Zurich, Switzerland4

Received 7 July 2003/ Accepted 3 September 2003

Human immunodeficiency virus type 1 (HIV-1) isolates from 20 chronically infected patients who participated in a structured treatment interruption (STI) trial were studied to determine whether viral fitness influences reestablishment of viremia. Viruses derived from individuals who spontaneously controlled viremia had significantly lower in vitro replication capacities than viruses derived from individuals that did not control viremia after interruption of antiretroviral therapy (ART), and replication capacities correlated with pre-ART and post-STI viral set points. Of note, no clinically relevant improvement of viral loads upon STI occurred. Virus isolates from controlling and noncontrolling patients were indistinguishable in terms of coreceptor usage, genetic subtype, and sensitivity to neutralizing antibodies. In contrast, viruses from controlling patients exhibited increased sensitivity to inhibition by chemokines. Sensitivity to inhibition by RANTES correlated strongly with slower replication kinetics of the virus isolates, suggesting a marked dependency of these virus isolates on high coreceptor densities on the target cells. In summary, our data indicate that viral fitness is a driving factor in determining the magnitude of viral rebound and viral set point in chronic HIV-1 infection, and thus fitness should be considered as a parameter influencing the outcome of therapeutic intervention in chronic infection.

* Corresponding author. Mailing address: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Ramistrasse 100, 8091 Zurich, Switzerland. Phone: 41-1-255-5976. Fax: 41-1-255-3291. E-mail: alexandra.trkola{at}usz.ch.

{dagger} Present address: Institute for Research in Biomedicine, 6500 Bellinzona, Switzerland.

{ddagger} Members of the Swiss HIV Cohort Study are listed in Acknowledgments.

Journal of Virology, December 2003, p. 13146-13155, Vol. 77, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.24.13146-13155.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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