Worldwide, 20 million people are infected with HTLV-1, a majority of which remain asymptomatic carriers (ACs) while others develop ATL or HAM/TSP with no effective treatment, vaccine or cure. The exact mechanism(s) of disease pathophysiology remain unresolved with a big question of high proviral load in HAM/TSP patients despite vigorous cellular immune response (primarily directed towards viral transactivator protein Tax)? Our initial studies implicated programmed death (PD)-1 receptor and its ligand, PD-L1 as potential underlying factors for observed immune cells' dysfunctions leading to viral persistence and disease progression, primarily in HAM/TSP patients. PD-1:PD-L1/PD-L2 are the members of immunoglobulin superfamily (IgSF) co-signaling molecules and have been linked with CD8 T-cell exhaustion during chronic viral infections. Several members of this family play critical role in regulating antigen-specific immune responses, and it is becoming increasingly evident that blocking multiple inhibitory receptors simultaneously improves T-cell based therapies. Therefore, we propose to investigate a comparative co-expression pattern of key IgSF negative regulators among carriers versus patients followed by standardizing of a blockade strategy to restore polyfunctionality, immune homeostasis, and cytolytic potential of antigen-specific T cells in HTLV-1 patient cohorts. To project advantage, this kind of therapeutic measure has shown promising results in other human diseases; however, it needs to be evaluated with respect to neuroinflammatory diseases especially those associated with chronic infection for which HTLV-1 provides a good model. While this approach should help in restoring functions of pre-existing antiviral immunity in patients, activating new CTLs to mimic polyclonal CD8 T-cell response found in ACs will be the key for a successful immunotherapeutic intervention of HTLV-associated diseases. Thus, we will identify a panel of HTLV-1 epitopes directly from the infected cells and validate in ACs to select potential neoepitopes capable of initiating a polyclonal response in chronically infected patients. The selected candidates from both approaches will then be coupled in a combined immunotherapy, which will be evaluated pre-clinically in a humanized (BLT) mouse model of HTLV-1 chronic infection. Our central hypothesis is that a combined immunotherapy coupled with immune checkpoint blockers and neo-epitopes derived from infected cells will restore existing T-cell functions while expanding protective CTLs in chronically infected patients. As a result of this, HTLV-1 proviral load and concomitant Tax expression will be reduced leading to decreased antigen threshold for the expansion of T cells with dysregulated functions and exhausted phenotype. The restoration of positive immunity within periphery will also lead to the reduced accumulation of activated T cells and inflammation within the CNS potentially ameliorating the disease. These studies will strengthen the potential of immunotherapeutic treatment options for HTLV-1 and will impact our understanding of other chronic infectious diseases of broader impact such as those associated with HBV, HCV, HIV-1, etc.
These studies will investigate approaches to restore immune cell functions and enhance protective anti-viral immunity during HTLV-associated diseases. This proposal also intends to accelerate the pre-clinical development of a novel emerging vaccine strategy, which could prevent significant complications of chronic HTLV-1 infection. Additional information derived will facilitate the development of novel immunotherapeutic initiatives to treat HTLV-induced neuroinflammatory disease as well as those of other etiologies.
|Sharma, Ravi Kumar; Sharma, Jyoti; Khan, Zafar K et al. (2018) Diminished TLR2-TLR9 mediated CD4+ T cell responses are associated with increased inflammation in intraocular tuberculosis. Sci Rep 8:13812|
|Dave, Rajnish S; Jain, Pooja; Byrareddy, Siddappa N (2018) Functional Meningeal Lymphatics and Cerebrospinal Fluid Outflow. J Neuroimmune Pharmacol 13:123-125|
|Mulherkar, Ria; Karabudak, Aykan; Ginwala, Rashida et al. (2018) In vivo and in vitro immunogenicity of novel MHC class I presented epitopes to confer protective immunity against chronic HTLV-1 infection. Vaccine 36:5046-5057|
|Dave, Rajnish S; Jain, Pooja; Byrareddy, Siddappa N (2018) Follicular Dendritic Cells of Lymph Nodes as Human Immunodeficiency Virus/Simian Immunodeficiency Virus Reservoirs and Insights on Cervical Lymph Node. Front Immunol 9:805|
|Dave, Rajnish S; Sharma, Ravi K; Muir, Roshell R et al. (2018) FDC:TFH Interactions within Cervical Lymph Nodes of SIV-Infected Rhesus Macaques. J Neuroimmune Pharmacol 13:204-218|
|Ginwala, Rashida; Caruso, Breanna; Khan, Zafar K et al. (2017) HTLV-1 Infection and Neuropathogenesis in the Context of Rag1-/-?c-/- (RAG1-Hu) and BLT Mice. J Neuroimmune Pharmacol 12:504-520|
|Pestell, Timothy G; Jiao, Xuanmao; Kumar, Mukesh et al. (2017) Stromal cyclin D1 promotes heterotypic immune signaling and breast cancer growth. Oncotarget 8:81754-81775|
|Sagar, Divya; Singh, Narendra P; Ginwala, Rashida et al. (2017) Antibody blockade of CLEC12A delays EAE onset and attenuates disease severity by impairing myeloid cell CNS infiltration and restoring positive immunity. Sci Rep 7:2707|
|Pustylnikov, Sergey; Dave, Rajnish S; Khan, Zafar K et al. (2016) Short Communication: Inhibition of DC-SIGN-Mediated HIV-1 Infection by Complementary Actions of Dendritic Cell Receptor Antagonists and Env-Targeting Virus Inactivators. AIDS Res Hum Retroviruses 32:93-100|
|Ginwala, Rashida; McTish, Emily; Raman, Chander et al. (2016) Apigenin, a Natural Flavonoid, Attenuates EAE Severity Through the Modulation of Dendritic Cell and Other Immune Cell Functions. J Neuroimmune Pharmacol 11:36-47|