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Published Online July 8, 2004
Science DOI: 10.1126/science.1098632

Reports

Submitted on April 1, 2004
Accepted on June 23, 2004

Integrase Inhibitors and Cellular Immunity Suppress Retroviral Replication in Rhesus Macaques

Daria J. Hazuda 1*, Steven D. Young 2*, James P. Guare 2, Neville J. Anthony 2, Robert P. Gomez 2, John S. Wai 2, Joseph P. Vacca 2, Larry Handt 3, Sherri L. Motzel 3, Hilton J. Klein 3, Geethanjali Dornadula 1, Robert M. Danovich 1, Marc V. Witmer 1, Keith A. A. Wilson 4, Lynda Tussey 4, William A. Schleif 4, Lori S. Gabryelski 4, Lixia Jin 5, Michael D. Miller 1, Danilo R. Casimiro 4, Emilio A. Emini 4, John W. Shiver 6

1 Department of Biological Chemistry, Merck Research Laboratories, Post Office Box 4, West Point, PA 19486, USA.
2 Department of Medicinal Chemistry, Merck Research Laboratories, Post Office Box 4, West Point, PA 19486, USA.
3 Department of Laboratory Animal Research, Merck Research Laboratories, Post Office Box 4, West Point, PA 19486, USA.
4 Department of Vaccine Research, Merck Research Laboratories, Post Office Box 4, West Point, PA 19486, USA.
5 Drug Metabolismand Pharmaceutical Research Merck Research Laboratories, Post Office Box 4, West Point, PA 19486, USA.
6 Department of Vaccine Research,Merck Research Laboratories, Post Office Box 4, West Point, PA 19486, USA.

* To whom correspondence should be addressed.
Daria J. Hazuda , E-mail: daria_hazuda{at}merck.com
Steven D. Young , E-mail: steve_young{at}merck.com

We describe the efficacy of L-870812, a novel inhibitor of HIV-1 and SIV integrase, in rhesus macaques infected with the simian-human immunodeficiency virus (SHIV) 89.6P. When initiated prior to CD4 cell depletion, L-870812 therapy mediated a sustained suppression of viremia, preserving CD4 levels and permitting the induction of virus-specific cellular immunity. L-870812 was also active in chronic infection; however, the magnitude and durability of the effect varied in conjunction with the pretreatment immune response and viral load. These studies provide a demonstration of integrase inhibitor activity in vivo and suggest that cellular immunity facilitates chemotherapeutic efficacy in retroviral infections.


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