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Originally published in Science Express on 8 July 2004
Science 23 July 2004:
Vol. 305. no. 5683, pp. 528 - 532
DOI: 10.1126/science.1098632
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Reports

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. Shiver4

We describe the efficacy of L-870812, an inhibitor of HIV-1 and SIV integrase, in rhesus macaques infected with the simian-human immunodeficiency virus (SHIV) 89.6P. When initiated before 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 demonstrate integrase inhibitor activity in vivo and suggest that cellular immunity facilitates chemotherapeutic efficacy in retroviral infections.

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 Metabolism and Pharmaceutical Research, Merck Research Laboratories, Post Office Box 4, West Point, PA 19486, USA.

* To whom correspondence should be addressed. E-mail: steve_young{at}merck.com, daria_hazuda{at}merck.com

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