The acquired immunodeficiency syndrome caused by HIV-1 is the leading cause of death in Africa and the fourth leading cause of death woridwide. The recent RV144 phase-3 trial (Thai trial) testing the efficacy of an AIDS vaccine consisting of a poxvirus vector (ALVAC) prime and protein boost demonstrated a modest efficacy where 25% ofthe vaccinated individuals were protected from HIV-1 infection. These results are highly encouraging, however the immune correlates for this protection are yet to be identified but suggest a role for non-neutralizing Ab in protection. Furthermore, the protection in the Thai trial appeared to be short lived (for the first six months) and there is a need for developing approaches that sustain immunological memory of vaccineelicited responses. Our ongoing studies in rhesus macaques demonstrated a similar protection from heterologous repetitive mucosal SIV challenges by a DNA prime and poxvirus (modified vaccinia Ankara) boost vaccine (DNA/MVA). In addition, co-delivery of granulocyte and macrophage colony stimulating factor (GM-CSF) DNA with our vaccine DNA significantly enhanced the protection mediated by the DNA/MVA vaccine from 25% to 70%. GM-CSF did not adjuvant the anti-viral CD8 T cell responses but enhanced the avidity of binding Ab specific to the Env and promoted generation of anti-viral IgA in rectal secretions. Importantly, the avidity of binding Ab against the challenge virus Env strongly correlated with enhanced protection against acquisition of SIV infection. These and results from other studies highlight an important role for other non-neutralizing activities of antibody in protection. The overall goals of this project are to identify the mechanisms of GM-CSF-mediated enhancement of protection against a mucosal SIV challenge and to test the effect of a protein boost for enhancing this protection against acquisition of heterologous repetitive intravaginal SIV challenges in rhesus macaques. In our specific aim 1, we will investigate the immune correlates for GM-CSF mediated enhanced protection. Here we will test the hypothesis that GM-CSF enhances the breadth, avidity, cytolytic activity and mucosal homing of anti-Env binding Ab in serum and mucosal secretions by modulating function of antigen presenting cells and T helper responses. In our specific aim 2, we will test whether addition of a protein boost, adjuvated with either alum or a combination of toll-like receptor ligands encapsulated in nanoparticles, to the GM-CSF-adjuvanted DNA/MVA vaccine will further enhance the longevitiy of protective immunity against acquisition of heterologous repetitive intravaginal SIV challenge.
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 world wide.
|Chan, Justin T H; Liu, Yanling; Khan, Srijit et al. (2018) A tyrosine sulfation-dependent HLA-I modification identifies memory B cells and plasma cells. Sci Adv 4:eaar7653|
|Jones, Andrew T; Chamcha, Venkateswarlu; Kesavardhana, Sannula et al. (2018) A Trimeric HIV-1 Envelope gp120 Immunogen Induces Potent and Broad Anti-V1V2 Loop Antibodies against HIV-1 in Rabbits and Rhesus Macaques. J Virol 92:|
|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:|
|Chea, Lynette Siv; Amara, Rama Rao (2017) Immunogenicity and efficacy of DNA/MVA HIV vaccines in rhesus macaque models. Expert Rev Vaccines 16:973-985|
|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|
|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|
|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|
Showing the most recent 10 out of 54 publications