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Journal of Virology, April 2007, p. 3414-3427, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.02453-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Replication-Competent Adenovirus-Human Immunodeficiency Virus (Ad-HIV) tat and Ad-HIV env Priming/Tat and Envelope Protein Boosting Regimen Elicits Enhanced Protective Efficacy against Simian/Human Immunodeficiency Virus SHIV89.6P Challenge in Rhesus Macaques{triangledown}

Thorsten Demberg,1 Ruth H. Florese,1 Megan J. Heath,1 Kay Larsen,2 Irene Kalisz,3 V. S. Kalyanaraman,3 Eun Mi Lee,3 Ranajit Pal,3 David Venzon,4 Richard Grant,2 L. Jean Patterson,1 Birgit Korioth-Schmitz,5 Adam Buzby,5 Dilani Dombagoda,5 David C. Montefiori,6 Norman L. Letvin,5 Aurelio Cafaro,7 Barbara Ensoli,7 and Marjorie Robert-Guroff1*

Vaccine Branch, National Cancer Institute, Bethesda, Maryland 20892,1 Washington National Primate Research Center, Seattle, Washington 98195,2 Advanced BioScience Laboratories, Inc., Kensington, Maryland 20895,3 Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland 20892,4 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115,5 Duke University Medical Center, Durham, North Carolina 27710,6 Istituto Superiore di Sanita, National AIDS Center, Rome, Italy7

Received 7 November 2006/ Accepted 9 January 2007

We previously demonstrated that replication-competent adenovirus (Ad)-simian immunodeficiency virus (SIV) recombinant prime/protein boost regimens elicit potent immunogenicity and strong, durable protection of rhesus macaques against SIVmac251. Additionally, native Tat vaccines have conferred strong protection against simian/human immunodeficiency virus SHIV89.6P challenge of cynomolgus monkeys, while native, inactivated, or vectored Tat vaccines have failed to elicit similar protective efficacy in rhesus macaques. Here we asked if priming rhesus macaques with replicating Ad-human immunodeficiency virus (HIV) tat and boosting with the Tat protein would elicit protection against SHIV89.6P. We also evaluated a Tat/Env regimen, adding an Ad-HIV env recombinant and envelope protein boost to test whether envelope antibodies would augment acute-phase protection. Further, expecting cellular immunity to enhance chronic viremia control, we tested a multigenic group: Ad-HIV tat, -HIV env, -SIV gag, and -SIV nef recombinants and Tat, Env, and Nef proteins. All regimens were immunogenic. A hierarchy was observed in enzyme-linked immunospot responses (with the strongest response for Env, followed by Gag, followed by Nef, followed by Tat) and antibody titers (with the highest titer for Env, followed by Tat, followed by Nef, followed by Gag). Following intravenous SHIV89.6P challenge, all macaques became infected. Compared to controls, no protection was seen in the Tat-only group, confirming previous reports for rhesus macaques. However, the multigenic group blunted acute viremia by approximately 1 log (P = 0.017), and both the multigenic and Tat/Env groups reduced chronic viremia by 3 and 4 logs, respectively, compared to controls (multigenic, P = 0.0003; Tat/Env, P < 0.0001). The strikingly greater reduction in the Tat/Env group than in the multigenic group (P = 0.014) was correlated with Tat and Env binding antibodies. Since prechallenge anti-Env antibodies lacked SHIV89.6P-neutralizing activity, other functional anti-Env and anti-Tat activities are under investigation, as is a possible synergy between the Tat and Env immunogens.

* Corresponding author. Mailing address: NIH, NCI, 41 Medlars Drive, Building 41, Room D804, Bethesda, MD 20892-5065. Phone: (301) 496-2114. Fax: (301) 402-0055. E-mail: guroffm{at}mail.nih.gov.

{triangledown} Published ahead of print on 17 January 2007.

Journal of Virology, April 2007, p. 3414-3427, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.02453-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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