The failure of Ad5 based HIV-1 vaccine in humans that is designed to elicit primarily antiviral T cells strongly suggests the need to develop novel vaccine approaches that generate high levels of anti-viral T cells with improved function as well as protective Ab. The goal of this project is to adjuvant the cellular and humoral immunity elicited by our DNA/MVA vaccine that has just entered phase II testing in humans in US. Specifically, we propose to target the CD40 pathway on dendritic cells (DC) and B cells using CD40L. Stimulation of CD40 on DC results in production of IFNg and IL-12 that are critical for generation of highly functional antiviral CDS response. Activation of B cells through CD40 is necessary for germinal center formation where affinitv maturation of B cells occurs leading to generation of high avidity Ab. Here, we will express CD40L on the surface of a SIV virus-like particle (CD40L-VLP). These CD40L-VLPs are potent activators of DC and B cells in vitro. In addition, they can be targeted to DC (through interaction between gpl20 on VLP and CD4 on DC) and allow presentation of Env in its native form that is critical for eliciting broadly cross-reactive neutralizing Ab.
In specific aim 1. we will test the potential of CD40L-adiuvanted DNA/MVA SIV vaccine to enhance control of a pathogenic SIV challenge. In addition, we will test whether delivering DNA by electroporation enhances the immunogenicity of the adluvanted and non-adiuvanted DN/VMVA vaccines. Recent studies from Dr. Rafi Ahmed's lab (PI of project 2) demonstrated that mTOR regulates memory T cell development and inhibition of this pathway following infection or vaccination using rapamycin enhances the magnitude and functional quality of antigen-specific CDS T cells. Rapamycin has also been shown to down regulate expression of CCR5 on CD4 T cells that results in marked reduction of HIV replication. This could be an added advantage for HIV vaccines, because the vaccine-elicited CCR5'virus-specific CD4 T cells may not be infected by the virus. Essentially we may be reducing the freguency of potential virus target cells while preserving the much-needed CD4 T cell helD following infection.
In specific aim 2, we will test the synergy between inhibiting mTOR and activating CD40 pathways for adjuvanting the immunogenicity and efficacy of DNA/MVA vaccines.

Public Health Relevance

WHO estimates that there are currently 32 million humans living with HIV/AIDS. Drugs and iniproved treatment regimens have successfully prolonged the lives of infected individuals in first world countries. However, these are not affordable for the vast majority of HIV-infected individuals. Even in developed nations these are limited by toxicity, affordability, the need for rigorous adherence to therapy and the emergence of drug resistant viruses. Thus, there is a great need to develop a safe and effective HIV vaccine that provides a low-cost, lowtoxicity solution to long-term control of viral replication - the main goal of this PPG.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI088575-03
Application #
8375933
Study Section
Special Emphasis Panel (ZAI1-RB-A)
Project Start
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$578,471
Indirect Cost
$238,344
Name
Emory University
Department
Type
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Velu, Vijayakumar; Mylvaganam, Geetha Hanna; Gangadhara, Sailaja et al. (2016) Induction of Th1-Biased T Follicular Helper (Tfh) Cells in Lymphoid Tissues during Chronic Simian Immunodeficiency Virus Infection Defines Functionally Distinct Germinal Center Tfh Cells. J Immunol 197:1832-42
Kannanganat, Sunil; Wyatt, Linda S; Gangadhara, Sailaja et al. (2016) High Doses of GM-CSF Inhibit Antibody Responses in Rectal Secretions and Diminish Modified Vaccinia Ankara/Simian Immunodeficiency Virus Vaccine Protection in TRIM5α-Restrictive Macaques. J Immunol 197:3586-3596
Kwa, Suefen; Sadagopal, Shanmugalakshmi; Shen, Xiaoying et al. (2015) CD40L-adjuvanted DNA/modified vaccinia virus Ankara simian immunodeficiency virus (SIV) vaccine enhances protection against neutralization-resistant mucosal SIV infection. J Virol 89:4690-5
Iyer, Smita S; Gangadhara, Sailaja; Victor, Blandine et al. (2015) Codelivery of Envelope Protein in Alum with MVA Vaccine Induces CXCR3-Biased CXCR5+ and CXCR5- CD4 T Cell Responses in Rhesus Macaques. J Immunol 195:994-1005
Chamcha, Venkateswarlu; Jones, Andrew; Quigley, Bernard R et al. (2015) Oral Immunization with a Recombinant Lactococcus lactis-Expressing HIV-1 Antigen on Group A Streptococcus Pilus Induces Strong Mucosal Immunity in the Gut. J Immunol 195:5025-34
Mylvaganam, Geetha H; Velu, Vijayakumar; Hong, Jung-Joo et al. (2014) Diminished viral control during simian immunodeficiency virus infection is associated with aberrant PD-1hi CD4 T cell enrichment in the lymphoid follicles of the rectal mucosa. J Immunol 193:4527-36
Kwa, Suefen; Lai, Lilin; Gangadhara, Sailaja et al. (2014) CD40L-adjuvanted DNA/modified vaccinia virus Ankara simian immunodeficiency virus SIV239 vaccine enhances SIV-specific humoral and cellular immunity and improves protection against a heterologous SIVE660 mucosal challenge. J Virol 88:9579-89
Araki, Koichi; Youngblood, Ben; Ahmed, Rafi (2013) Programmed cell death 1-directed immunotherapy for enhancing T-cell function. Cold Spring Harb Symp Quant Biol 78:239-47
Xu, Xiaojin; Ye, Lilin; Araki, Koichi et al. (2012) mTOR, linking metabolism and immunity. Semin Immunol 24:429-35
Araki, Koichi; Ellebedy, Ali H; Ahmed, Rafi (2011) TOR in the immune system. Curr Opin Cell Biol 23:707-15

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