Two of the most critical challenges in developing an effecfive AIDS vaccine are to understand how to induce durable immunity at mucosal sites and to define the eariy interactions between HIV and the immune system. In Project 3 we will address both of these issues using the rhesus macaque (RM) model of SIV infection. The precise mechanism by which an AIDS vaccine can confer protective immunity is not known but there is now a general consensus that an effective vaccine should induce both the cellular and humoral arms of the immune system, in particular at the mucosal sites. Recent data from the RV-144 AIDS vaccine trial in Thailand suggest a potential role for antibody in protection from HIV infection. One striking finding from the RV-144 trial was that protection was short-lived and was mostly seen during the first year after vaccination. Thus, a major goal in developing an effective vaccine is to understand how to generate long-lived mucosal immunity. (5D4 T follicular helper (TFH) cells are critical for generating potent and long-lasting anfibody responses and in this project we will determine their role in generating protective humoral immunity following vaccination and infecfion. In our specific aim 1, we will test the hypothesis that long-term humoral immunity is critically dependent on CD4 TFH cells and that the efficient generation of these cells is an essenfial and obligatory component of an effective HIV vaccine. We will examine the magnitude, quality and persistence of SIV specific CD4 TFH cells in both peripheral and mucosal sites after vaccination and determine its correlation to B cell responses. These studies will examine CD4 TFH responses in RMs immunized with DNA/MVA vaccines adjuvanted with GM-CSF (Project 1) and SIV protein immunizafions adjuvanted with TLRs encapsulated in nanoparticles (Project 2). These studies will define which vaccine regimen is most effective in inducing CD4 TFH cells in peripheral and mucosal sites and how the different adjuvants modulate the TFH response and their influence on functional quality and longevity of humoral immunity. In our specific aim 2, we will test the hypothesis that HIV/SIV immunopathogenesis normally precludes the development of a broadly neutralizing anfibody response, but this can be counteracted by immunizafion to generate strong TFH responses before infection. We will determine the suscepfibility of TFH celts to SIV infection and study the infiuence of vaccinafion on their status following infecfion, and the relafionship between the level of virus replicafion in CD4 TFH cells and the main features of SIV infection, including the immune response to the virus and the progression to AIDS.

Public Health Relevance

The acquired immunodeficiency caused by HIV-1 is the leading cause of death in Africa and the fourth leading cause of death woridwide. The overall goal of this project is to develop an effective vaccine to control HIV/AIDS.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-LR-A (M2))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
United States
Zip Code
Kasturi, Sudhir Pai; Kozlowski, Pamela A; Nakaya, Helder I et al. (2017) Adjuvanting a Simian Immunodeficiency Virus Vaccine with Toll-Like Receptor Ligands Encapsulated in Nanoparticles Induces Persistent Antibody Responses and Enhanced Protection in TRIM5? Restrictive Macaques. J Virol 91:
Chamcha, Venkateswarlu; Kannanganat, Sunil; Gangadhara, Sailaja et al. (2016) Strong, but Age-Dependent, Protection Elicited by a Deoxyribonucleic Acid/Modified Vaccinia Ankara Simian Immunodeficiency Virus Vaccine. Open Forum Infect Dis 3:ofw034
Cartwright, Emily K; Spicer, Lori; Smith, S Abigail et al. (2016) CD8(+) Lymphocytes Are Required for Maintaining Viral Suppression in SIV-Infected Macaques Treated with Short-Term Antiretroviral Therapy. Immunity 45:656-668
Yu, Cuiling; Liu, Yanling; Chan, Justin Tze Ho et al. (2016) Identification of human plasma cells with a lamprey monoclonal antibody. JCI Insight 1:
Havenar-Daughton, Colin; Reiss, Samantha M; Carnathan, Diane G et al. (2016) Cytokine-Independent Detection of Antigen-Specific Germinal Center T Follicular Helper Cells in Immunized Nonhuman Primates Using a Live Cell Activation-Induced Marker Technique. J Immunol 197:994-1002
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 TRIM5?-Restrictive Macaques. J Immunol 197:3586-3596
Locci, Michela; Wu, Jennifer E; Arumemi, Fortuna et al. (2016) Activin A programs the differentiation of human TFH cells. Nat Immunol 17:976-84
Smith, S Abigail; Kilgore, Katie M; Kasturi, Sudhir Pai et al. (2016) Signatures in Simian Immunodeficiency Virus SIVsmE660 Envelope gp120 Are Associated with Mucosal Transmission but Not Vaccination Breakthrough in Rhesus Macaques. J Virol 90:1880-7
Cho, Alice; Wrammert, Jens (2016) Implications of broadly neutralizing antibodies in the development of a universal influenza vaccine. Curr Opin Virol 17:110-5
Santangelo, Philip J; Rogers, Kenneth A; Zurla, Chiara et al. (2015) Whole-body immunoPET reveals active SIV dynamics in viremic and antiretroviral therapy-treated macaques. Nat Methods 12:427-32

Showing the most recent 10 out of 51 publications