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Journal of Virology, October 2005, p. 12321-12331, Vol. 79, No. 19
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.19.12321-12331.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Vectored Gag and Env but Not Tat Show Efficacy against Simian-Human Immunodeficiency Virus 89.6P Challenge in Mamu-A*01-Negative Rhesus Monkeys

Xiaoping Liang,1* Danilo R. Casimiro,1 William A. Schleif,1 Fubao Wang,1 Mary-Ellen Davies,1 Zhi-Qiang Zhang,1 Tong-Ming Fu,1 Adam C. Finnefrock,1 Larry Handt,1 Michael P. Citron,1 Gwendolyn Heidecker,1 Aimin Tang,1 Minchun Chen,1 Keith A. Wilson,1 Lori Gabryelski,1 Michael McElhaugh,1 Anthony Carella,1 Cheryl Moyer,1 Lingyi Huang,1 Salvatore Vitelli,1 Deepa Patel,1 Jing Lin,1 Emilio A. Emini,2 and John W. Shiver1

Merck Research Laboratories, West Point, Pennsylvania,1 International AIDS Vaccine Initiative, New York, New York2

Received 11 March 2005/ Accepted 6 July 2005

Simian-human immunodeficiency virus (SHIV) challenge studies in rhesus macaques were conducted to evaluate the efficacy of adenovirus-based vaccines in the context of different major histocompatibility complex class I genetic backgrounds and different vaccine compositions. Mamu-A*01 allele-negative rhesus monkeys were immunized with one of the following vaccine constructs: (i) replication-defective recombinant adenovirus type 5 (Ad5) expressing human immunodeficiency virus type 1 (HIV-1) Tat (Ad5/HIVTat); (ii) Ad5 vector expressing simian immunodeficiency virus (SIV) Gag (Ad5/SIVGag); (iii) Ad5 vector expressing the truncated HIV-1jrfl Env, gp140 (Ad5/gp140_jrfl); (iv) Ad5 vector expressing the SHIV-89.6P gp140 (Ad5/gp140_89.6P); or (v) the combination of Ad5/SIVGag and Ad5/gp140_jrfl. Following intravenous challenge with SHIV-89.6P, only those cohorts that received vaccines expressing Gag or Env exhibited an attenuation of the acute viremia and associated CD4-cell lymphopenia. While no prechallenge neutralizing antibody titers were detectable in either Ad5/gp140-vaccinated group, an accelerated neutralizing antibody response was observed in the Ad5/gp140_89.6P-vaccinated group upon viral challenge. The set-point viral loads in the Ad5/SIVGag- and Ad5/gp140_jrfl-vaccinated groups were associated with the overall strength of the induced cellular immune responses. To examine the contribution of Mamu-A*01 allele in vaccine efficacy against SHIV-89.6P challenge, Mamu-A*01-positive monkeys were immunized with Ad5/SIVGag. Vaccine-mediated protection was significantly more pronounced in the Mamu-A*01-positive monkeys than in Mamu-A*01-negative monkeys, suggesting the strong contributions of T-cell epitopes restricted by the Mamu-A*01 molecule. The implications of these results in the development of an HIV-1 vaccine will be discussed.

* Corresponding author. Mailing address: Merck Research Laboratories, P. O. Box 4, WP16-306, West Point, PA 19486. Phone: 215 652 8215. Fax: 215 652 8215. E-mail: xiaoping_liang{at}merck.com.

Journal of Virology, October 2005, p. 12321-12331, Vol. 79, No. 19
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.19.12321-12331.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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