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Journal of Virology, July 2009, p. 7166-7175, Vol. 83, No. 14
0022-538X/09/$08.00+0     doi:10.1128/JVI.00374-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Delivery of Human Immunodeficiency Virus Vaccine Vectors to the Intestine Induces Enhanced Mucosal Cellular Immunity{triangledown} ,{dagger}

Lingshu Wang,1,{ddagger} Cheng Cheng,1,{ddagger} Sung-Youl Ko,1 Wing-Pui Kong,1 Masaru Kanekiyo,1 David Einfeld,2 Richard M. Schwartz,1 C. Richter King,2 Jason G. D. Gall,2 and Gary J. Nabel1*

Vaccine Research Center, NIAID, National Institutes of Health, Bldg. 40, Room 4502, MSC-3005, 40 Convent Drive, Bethesda, Maryland 20892-3005,1 GenVec, Inc., 65 West Watkins Mill Rd., Gaithersburg, Maryland 208782

Received 19 February 2009/ Accepted 30 April 2009

Effective vaccines for human immunodeficiency virus type 1 (HIV-1) will likely need to stimulate protective immunity in the intestinal mucosa, where HIV-1 infection causes severe CD4+ T-cell depletion. While replication-competent recombinant adenovirus (rAd) vectors can stimulate adenovirus-specific mucosal immunity after replication, oral delivery of replication-defective rAd vectors encoding specific immunogens has proven challenging. In this study, we have systematically identified barriers to effective gut delivery of rAd vectors and identified sites and strategies to induce potent cellular and humoral immunity. Vector-mediated gene transfer by rAd5 was susceptible to low-pH buffer, gastric and pancreatic proteases, and extracellular mucins. Using ex vivo organ explants, we found that transduction with rAd5 was highest in the ileum and colon among all intestinal segments. Transgene expression was 100-fold higher after direct surgical introduction into the ileum than after oral gavage, with rAd5 showing greater potency than the rAd35 or the rAd41 vector. A single immunization of rAd5 encoding HIV-1 gp140B to the ileum stimulated potent CD8+ T-cell responses in the intestinal and systemic compartments, and these responses were further enhanced by intramuscular rAd5 boosting. These studies suggest that induction of primary immune responses by rAd5 gut immunization and subsequent systemic boosting elicits potent antigen-specific gut mucosal responses.

* Corresponding author. Mailing address: Vaccine Research Center, NIAID, National Institutes of Health, Bldg. 40, Room 4502, MSC-3005, 40 Convent Drive, Bethesda, MD 20892-3005. Phone: (301) 496-1852. Fax: (301) 480-0274. E-mail: gnabel{at}nih.gov

{triangledown} Published ahead of print on 6 May 2009.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

{ddagger} These authors contributed equally to this report.

Journal of Virology, July 2009, p. 7166-7175, Vol. 83, No. 14
0022-538X/09/$08.00+0     doi:10.1128/JVI.00374-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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