Integrase inhibitors and cellular immunity suppress retroviral replication in rhesus macaques.
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.
Hazuda
Daria J
DJ
Department of Biological Chemistry, Merck Research Laboratories, Post Office Box 4, West Point, PA 19486, USA. daria_hazuda@merck.com
Young
Steven D
SD
Guare
James P
JP
Anthony
Neville J
NJ
Gomez
Robert P
RP
Wai
John S
JS
Vacca
Joseph P
JP
Handt
Larry
L
Motzel
Sherri L
SL
Klein
Hilton J
HJ
Dornadula
Geethanjali
G
Danovich
Robert M
RM
Witmer
Marc V
MV
Wilson
Keith A A
KA
Tussey
Lynda
L
Schleif
William A
WA
Gabryelski
Lori S
LS
Jin
Lixia
L
Miller
Michael D
MD
Casimiro
Danilo R
DR
Emini
Emilio A
EA
Shiver
John W
JW
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D024882:Drug Resistance, Viral; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D007111:Immunity, Cellular; D019429:Integrase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000821:virology; D008253:Macaca mulatta; D009154:Mutation; D009287:Naphthyridines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D019562:Viral Load; D014766:Viremia / Q000188:drug therapy; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D019429:Integrase Inhibitors; C488294:L870812; D009287:Naphthyridines; D019427:HIV Integrase; D019426:Integrases