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* Vaccine Branch and
Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Washington National Primate Research Center, University of Washington, Seattle, WA 98195; and
Istituto Superiore di Sanita, National AIDS Center, Rome, Italy
Previously, chronic-phase protection against SHIV89.6P challenge was significantly greater in macaques primed with replicating adenovirus type 5 host range mutant (Ad5hr) recombinants encoding HIVtat and env and boosted with Tat and Env protein compared with macaques primed with multigenic adenovirus recombinants (HIVtat, HIVenv, SIVgag, SIVnef) and boosted with Tat, Env, and Nef proteins. The greater protection was correlated with Tat- and Env-binding Abs. Because the macaques lacked SHIV89.6P-neutralizing activity prechallenge, we investigated whether Ab-dependent cellular cytotoxicity (ADCC) and Ab-dependent cell-mediated viral inhibition (ADCVI) might exert a protective effect. We clearly show that Tat can serve as an ADCC target, although the Tat-specific activity elicited did not correlate with better protection. However, Env-specific ADCC activity was consistently higher in the Tat/Env group, with sustained cell killing postchallenge exhibited at higher levels (p < 0.00001) for a longer duration (p = 0.0002) compared with the multigenic group. ADCVI was similarly higher in the Tat/Env group and significantly correlated with reduced acute-phase viremia at wk 2 and 4 postchallenge (p = 0.046 and 0.011, respectively). Viral-specific IgG and IgA Abs in mucosal secretions were elicited but did not influence the outcome of the i.v. SHIV89.6P challenge. The higher ADCC and ADCVI activities seen in the Tat/Env group provide a plausible mechanism responsible for the greater chronic-phase protection. Because Tat is known to enhance cell-mediated immunity to coadministered Ags, further studies should explore its impact on Ab induction so that it may be optimally incorporated into HIV vaccine regimens.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute and by National Institutes of Health, National Institute of Allergy and Infectious Diseases Simian Vaccine Evaluation Contract N01-AI-15431 to the University of Washington.
2 Address correspondence and reprint requests to Dr. Marjorie Robert-Guroff, National Cancer Institute, National Institutes of Health, 41 Medlars Drive, Building 41, Room D804, Bethesda, MD 20892-5065. E-mail address: guroffm{at}mail.nih.gov
3 Abbreviations used in this paper: Ad, adenovirus; ADCC, Ab-dependent cellular cytotoxicity; ADCVI, Ab-dependent cell-mediated virus inhibition; Ad5hr, Ad type 5 host range mutant; RFADCC, rapid fluorometric ADCC assay; MOI, multiplicity of infection; ABL, Advanced BioScience Laboratories; RT, room temperature; KPL, Kirkegaard and Perry Laboratories; huPBMC, human PBMC; IFA, immunofluorescence assay.
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