Based on a multitude of data there are several features desired in an HIV Vaccine immunogen. Such animmunogen should induce strong and broad humoral and cellular immunity. Furthermore, as HIV is ingeneral a sexually transmitted disease and the cells of the gut are preferentially targeted for viraldestruction, an immunogen should be capable of inducing in particular mucosal as well as systemic immuneresponses. Currently there is no approach that can be simply administered that induces such a response.In this regard, Dr. Weiner's laboratory first reported that they could redirect immune cells in vivo usingchemokines encoded as part of a DMAvaccine cocktail, and recent work further confirmed and elegantlyextended these findings through modification of vaccine induced immune cell trafficking by utilizingchemokines (immune trafficking signals) to attract peripheral immune cell populations. It is now the goal ofthis application to extend this work and develop a mucosal vaccine strategy that will result in the redirectionof cells of the mucosal compartment in response to a DNA vaccine administered in the systemiccompartment. Our preliminary data support that this strategy generates features of mucosal immunity bysystemic vaccination. This application will further investigate this novel approach in this exceptionallyimportant area of vaccine development. We will study the ability of specific chemokines as DNA vaccineadjuvants to modulate immune cell trafficking and redirect effector T and B cell responses to mucosal sites.There are 4 Specific Aims outlined in Project 1 of this program that will address the following questions:First, will delivery of chemokine immunoadjuvants systemically by DNA vaccines induce antigen specificimmune responses in mucosal sites, and secondly, can mucosal-derived chemokine-inducedimmunogenicity be explained by a mechanism in which chemokines induce 'retrafficking' of organ specifichoming routes? Alternatively, is it such that the 'imprinting' dogma for peripheral/mucosal immune cells, infact, is reversible, resulting from chemokine-induced activation and 're-education' of target cells displayingnew homing potentials. Finally, we will test whether chemokine adjuvants can elicit physiologically relevantcellular and humoral immune responses that can protect mice from a lethal mucosal challenge. This projectwill also generate all constructs for the macaque studies for Project 2 and support the polyfunctional flowstudies in Project 3. These studies have great significance for our basic understanding of lymphocytehoming to the gut, mucosal phenotype commitment and for the development of an HIV vaccine that deliversantigens to generate mucosal immunity.
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