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J Virol, February 1998, p. 1052-1059, Vol. 72, No. 2
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Induction of Neutralizing Antibodies to T-Cell Line-Adapted and Primary Human Immunodeficiency Virus Type 1 Isolates with a Prime-Boost Vaccine Regimen in Chimpanzees

Susan Zolla-Pazner,1,2,* Michael Lubeck,3,dagger Serena Xu,2 Sherri Burda,2 Robert J. Natuk,4 Faruk Sinangil,5 Kathelyn Steimer,5,Dagger Robert C. Gallo,6,§ Jorg W. Eichberg,7 Thomas Matthews,8 and Marjorie Robert-Guroff6

Veterans Affairs Medical Center1 and New York University Medical Center,2 New York, New York; Wyeth-Ayerst Research, Radnor, Pennsylvania3; Wyeth-Lederle Vaccines and Pediatrics, Pearl River, New York4; Chiron Corporation, Emeryville, California5; National Cancer Institute, Bethesda, Maryland6; Dutch Primate Center, Rijswijk, The Netherlands7; and Duke University Medical Center, Durham, North Carolina8

Received 21 July 1997/Accepted 24 October 1997

Five chimpanzees were immunized by administration of one or more intranasal priming doses of one to three recombinant adenoviruses containing a gp160 insert from human immunodeficiency virus type 1 (HIV-1) MN (HIV-1MN) followed by one or more boosts of recombinant HIV-1SF2 gp120 delivered intramuscularly with MF59 adjuvant. This regimen resulted in humoral immune responses in three of five animals. Humoral responses included immunochemically active anti-HIV-1 antibodies (Abs) directed to recombinant gp120 and neutralizing Abs reactive with T-cell-line-adapted HIV-1MN and HIV-1SF2. In addition, neutralizing activity was detected to the two homologous primary isolates and to two of three heterologous primary isolates which, like the immunizing strains, can use CXCR4 as a coreceptor for infection. The three animals with detectable neutralizing Abs and a fourth exhibiting the best cytotoxic T-lymphocyte response were protected from a low-dose intravenous challenge with a cell-free HIV-1SF2 primary isolate administered 4 weeks after the last boost. Animals were rested for 46 weeks and then rechallenged, without a boost, with an eightfold-higher challenge dose of HIV-1SF2. The three animals with persistent neutralizing Abs were again protected. These data show that a strong, long-lived protective Ab response can be induced with a prime-boost regimen in chimpanzees. The data suggest that in chimpanzees, the presence of neutralizing Abs correlates with protection for animals challenged intravenously with a high dose of a homologous strain of HIV-1, and they demonstrate for the first time the induction of neutralizing Abs to homologous and heterologous primary isolates.

* Corresponding author. Mailing address: c/o Veterans Affairs Medical Center, Room 18124No, 423 E. 23rd St., New York, NY 10010. Phone: (212) 263-6769. Fax: (212) 951-6321. E-mail: Zollas01{at}mcrcr6.med.nyu.edu.

dagger Present address: Wyeth-Lederle Vaccines and Pediatrics, Marietta, PA 17547.

Dagger Deceased.

§ Present address: Institute of Human Virology, Baltimore, MD 21201.




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