Vaccine 28 (2010) 5676–5685 Contents lists available at ScienceDirect Vaccine journal homepage: www.elsevier.com/locate/vaccine Evaluation of yellow fever virus 17D strain as a new vector for HIV-1 vaccine development David Franco a , Wenjing Li c , Fang Qing a , Cristina T. Stoyanov b , Thomas Moran c , Charles M. Rice b , David D. Ho a,∗ a Aaron Diamond AIDS Research Center, The Rockefeller University, 455 First Ave., 7th Floor, New York, NY 10016, USA b Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, 1230 York Ave., New York, NY 10065, USA c Department of Microbiology, Mt. Sinai School of Medicine, New York, NY 10029, USA article info Article history: Received 16 March 2010 Received in revised form 8 June 2010 Accepted 15 June 2010 Available online 29 June 2010 Keywords: Yellow fever virus 17D HIV-1 p24 Vaccine abstract The failure to develop an effective vaccine against HIV-1 infection has led the research community to seek new ways of raising qualitatively different antibody and cellular immune responses. Towards this goal, we investigated the yellow fever 17D vaccine strain (YF17D), one of the most effective vaccines ever made, as a platform for HIV-1 vaccine development. A test antigen, HIV-1 p24 (clade B consen- sus), was inserted near the 5 ′ end of YF17D, in frame and upstream of the polyprotein (YF-5 ′ /p24), or between the envelope and the first non-structural protein (YF-E/p24/NS1). In vitro characterization of these recombinants indicated that the gene insert was more stable in the context of YF-E/p24/NS1. This was confirmed in immunogenicity studies in mice. CD8 + IFN- T-cell responses against p24 were elicited by the YF17D recombinants, as were specific CD4 + T cells expressing IFN- and IL-2. A balanced CD4 + and CD8 + T-cell response was notable, as was the polyfunctionality of the responding cells. Finally, the protective efficacy of the YF17D recombinants, particularly YF-E/p24/NS1, in mice challenged with a vaccinia expressing HIV-1 Gag was demonstrated. These results suggest that YF17D warrants serious consideration as a live-attenuated vector for HIV-1 vaccine development. © 2010 Elsevier Ltd. All rights reserved. 1. Introduction The HIV/AIDS pandemic has become part of the contemporary global landscape. Few predicted its effect on mortality and mor- bidity or its devastating social and economic consequences. Every day, an estimated 14,000 people become newly infected by HIV-1, with more than 95% of the new infections occurring in under- developed regions of the world. AIDS is the leading cause of death in Sub-Saharan Africa, where at least two-thirds of infected per- sons live [1]. There is an urgent need for the development of a safe, effective, and affordable vaccine against HIV-1 for worldwide use. Given the failure of the recombinant adenovirus type-5 (Ad5) vaccine to protect against HIV-1 infection in the STEP trial [2], new approaches are being sought. One candidate for serious considera- tion is YF17D, the live-attenuated yellow fever virus (YFV) vaccine strain that has been successfully used in hundreds of millions of humans for over seven decades. Some of the outstanding prop- ∗ Corresponding author. Tel.: +1 212 448 5100; fax: +1 212 725 1126. E-mail address: DHo@ADARC.org (D.D. Ho). erties of this vaccine include limited viral replication in the host but significant expansion and dissemination, yielding a robust and long-lived immune response [3]. YF17D also induces a significant T-cell response [3–5]. The vaccine is inexpensive, administered in a single dose and involves well-established production methods and quality-control procedures, which include a primate neurovir- ulence safety assay. The YF17D backbone has been used recently to develop recombinant live-attenuated vaccine candidates against several flavivirus-mediated diseases, including Japanese encephali- tis, dengue serotypes 1–4, and West Nile encephalitis [6–12]. In this study, we explored YF17D as a new HIV-1 vaccine platform. The clade B consensus Gag p24 sequence was introduced into the YF17D genome near the 5 ′ end, in frame and upstream of the polyprotein (YF-5 ′ /p24), or between the envelope protein (E) and the first non-structural protein (NS1) (YF-E/p24/NS1). The latter strategy was already successfully used for the insertion of Lassa virus glycoproteins in the YF17D backbone [13] and recently Bonaldo et al. [14] inserted SIV gag in a similar position. The YF17D recombinants were subsequently extensively characterized in vitro and in vivo. To our knowledge, this is the first in-depth immunological study probing YFV as a potential HIV-1 vaccine can- didate. 0264-410X/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2010.06.052