Developing an effective HIV vaccine presents extraordinary challenges given the diversity of the virus and the need for inducing both T and B cell responses that can provide broad coverage, have the right functional qualities and are long-lasting. During the past decade there has been substantial progress in developing various vaccine vectors and prime-boost combinations for inducing effective responses against HIV. However, it is critical to improve upon these promising vaccine strategies and to design novel approaches for enhancing vaccine-induced immunity. We have recently made the unexpected and surprising observation that rapamycin, a drug that targets mTOR (mammalian target of rapamycin) and is commonly used in transplant recipients as an imunosuppressive agent, can actually enhance not only the magnitude but also the functional qualities of vaccine-induced virus specific memory T cells. This adjuvant effect of rapamycin was seen in both mice and in non-human primates. We have also shown that rapamycin acts intrinsically in antigen specific T cells and identified mTOR as a major regulator of memory T cell differentiation. Thus, our working hypothesis is that targeting mTOR presents a novel strategy of modulating both the quantity and quality of vaccine-induceti memory Tcells. In addition to regulating memory T cell differentiation rapamycin can also decrease expression of CCR5, the HIV co-receptor, on activated CD4 T cells. Here we propose to modulate the mTOR pathway during vaccination to enhance generation of highly polyfunctional virus-specific CDS T cells and to induce virus-specific CD4 T cells that are CCR5'? and are less susceptible to HIV/SIV infection. Taken together such a vaccination strategy may lead to enhanced control of HIV/SIV infection. To achieve our goal, we will investigate two important effects of rapamycin in rhesus macaques;1) its safety and adjuvant effect in enhancing immunogenicity of AIDS vaccines and 2) its ability to enhance protection against a pathogenic SIV challenge.

Public Health Relevance

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI088575-03
Application #
8375934
Study Section
Special Emphasis Panel (ZAI1-RB-A)
Project Start
Project End
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$468,281
Indirect Cost
$192,943
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
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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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