For the last several years our frontier area of research has been on the microbial pathogenesis and therapy of infectious diseases including retroviruses and opportunistic infections. The current research efforts primarily focus on defining the mechanism of virus-induced neuroinflammation and demyelination in the central and peripheral nervous system in order to identify potential diagnostic markers and targets for therapeutic intervention. The model pathogen under study is human T cell leukemia virus type 1 (HTLV-1) that causes both immune and CNS disease. HTLV-1 is a human retrovirus that infects more than 20 million people worldwide predominantly in tropical areas. HTLV-1, although the first human retrovirus discovered, has received far less attention than human immunodeficiency virus type 1 (HIV-1) and many aspects of its immunological and molecular pathogenesis remain unresolved. HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP) is a progressive debilitating neurological disorder. In many ways, it resembles multiple sclerosis (MS), an autoimmune disease of the brain. The HTLV-1 transcriptional transactivator protein Tax is the oncogenic protein of the virus and performs a variety of functions both intracellularly and extracellularly.
The progression of HAM/TSP is suggested to be due, in part, to the ability of Tax to work as an extracellular effector molecule. Furthermore, a majority of the immune response (humoral and cell-mediated) in HAM/TSP patients is directed against Tax, indicating that Tax is available for immune recognition. However, the mechanism of Tax cross-presentation and its direct role in neurodegeneration remained uncharacterized. We are addressing these issues by using a novel transgenic mouse (HHD II/DTR-Tg) model developed recently with a chimeric HTLV-1 viral infection and disease progression. The transgenic strain will allow us to perform the HLA-A2.1 restricted Tax11-19-specific CTL studies in the absence and presence of dendritic cells (DCs). Efforts are being made to utilize this model as a tool to study the role of Tax and other viral factors as well as the components of the host immune response that may play important roles in the neuropathogenesis associated with HAM/TSP. The knowledge gained may be directly linked to clinical application
Other areas of research are HIV-1 therapeutics and microbicide development. We have developed collaborative INDO-US programs (MOUs) with a view to develop a new HIV-1 cohort (HIV clade C etc.) for HIV-1 genotyping, sequencing and therapeutic guidelines in HAART resistance in patients.
Selected Research Publications:
"Depletion of dendritic cells enhances susceptibility to cell-free but not cell-associated infection of HTLV-1 in CD11c-DTR-transgenic mice"
Rahman S, Manuel S, Khan ZK, Wigdahl B, Tangy F, Acheampong E, and P Jain
Journal of Immunology, 184: 1-9, 2010.
"Structural and functional studies of CCAAT/enhancer binding sites within the human immunodeficiency type 1 subtype C LTR"
Liu Y, Nonnemacher MR, Stauff DL, Li L, Banerjee A, Irish B, Rajagopalan N, Suchitra JB, Khan ZK, Ranga UK, and B Wigdahl
Biomedicine and Pharmacotherapy, in press, 2010.
"HTLV-1 Tax mediated downregulation of miRNAs associated with chromatin remodeling factors in stably integrated CD4+ T cell line"
Rahman S, Jain P, Quann K, Pandya D, Khan ZK, and B Wigdahl
Virology, submitted, 2010.
"Trafficking of immune cells across the blood-brain barrier"
Acheampong E, Rahman S, Manuel S, Khan ZK, and P Jain
Journal of Neuroimmunology, under revision, 2010.
"Role of resident CNS cell populations in HTLV-1-associated neuroinflammatory disease"
Lepoutre V, Jain P, Quann K, Wigdahl B, and ZK Khan
Frontiers in Bioscience, 14: 1152-1168, 2009.
"Molecular mechanisms of neurodegenerative diseases induced by human retroviruses"
Irish BP, Khan ZK, Jain P, Nonnemacher MR, Pirrone V, Rahman S, Rajagopalan N, Suchitra JB, Mostoller K and B Wigdahl
Journal of Infectious Diseases, 5: 238-265, 2009.
"DC-SIGN a potential target to block HTLV-1 transmission and infection"
Jain P, Manuel S, Khan ZK, Ahuja J, and B Wigdahl
Journal of Virology, 83: 10908-10921, 2009.
"Presentation of HTLV-1 Tax protein by dendritic cells: the underlying mechanism of HTLV-1 associated neuroinflammatory disease"
Manuel S, Schell T, Acheampong E, Rahman S, Khan ZK, and P Jain
Journal of Leukocyte Biology, 86: 1205-1216, 2009.
"Mortality among HIV-infected patients in resource limited settings: A case controlled analysis of inpatients at a community care center"
Rajgopalan N, Suchitra JB, Shet A, Khan ZK, Martin-Garcia J, Nonnemacher MR, Jacobson JM, and B Wigdahl
American Journal of Infectious Diseases, 5: 226-231, 2009.
"Modulation of dendritic cell maturation and function by the Tax protein of human T cell leukemia virus type 1"
Jain P, Ahuja J, Khan ZK, Shimizu S, Meucci O, Jennings S, and B Wigdahl
Journal of Leukocyte Biology, 82: 44-56, 2007.
"A novel high throughput quantum dot-based fluorescence assay for quantitation of virus binding and attachment"
Kampani K, Quann K, Ahuja J, Wigdahl B, Khan ZK, and P Jain.
Journal of Virological Methods, 141: 125-132, 2007.
"Induction of proinflammatory cytokines by human T cell leukemia virus type 1 Tax protein as determined by multiplexed cytokine protein array analyses of human dendritic cells"
Ahuja J, Lepoutre V, Wigdahl B, Khan ZK, and P Jain
Biomedicine and Pharmacotherapy, 61: 201-208, 2007.
"Dendritic cells in autoimmune diseases and neuroinflammatory disorders"
Manuel S, Rahman S, Wigdahl B, Khan ZK, and P Jain
Frontiers in Bioscience, 12: 4315-4335, 2007.
"Identification of HTLV-1 Tax amino acid signals and cellular factors involved in secretion of the viral oncoprotein"
Jain P, Mostoller K, Flaig KE, Ahuja J, Alefantis T, Khan ZK, and B Wigdahl
Journal of Biological Chemistry, 282: 34581-34593, 2007.
"New insights into the pathogenesis, diagnosis, and treatment of human T cell leukemia virus type 1-induced disease"
Pandya D, Rahman S, Wigdahl B, Khan ZK, and P Jain
Future Virology, 2: 481-493, 2007.
Patents:
"Isolation of bivittoside D from sea cucumber and activity thereof"
Lakshmi V, Pandey K, Saxena A, Madhusudanan KP, Srivastava MN, Khan ZK, Jain P, Gupta G, and JD Dhar.
US Patent # U015092-8, 2004.
"A process for the preparation of 5-bromo-6-methane sulfonamido-1-phenyl-9H-pyrido (3,4-b) indoles useful as antifungal agents"
Agarwal A, Agarwal SK, Shukla PK, and ZK Khan.
Patent # 019/DEL/93,1993.
"A process for the preparation of 6-acetamido-5-bromo-1-substituted-9H-pyrido (3,4-b) indoles, useful as antifungal agents"
Agarwal A, Agarwal SK, Shukla PK, and ZK Khan.
Patent # 018/DEL/93,1993.
"A process for the preparation of 7-bromo-1-phenyl-8-methane sulfonamido-9H-pyrido (3,4-b) indoles useful as antifungal agents"
Agarwal A, Agarwal SK, Shukla PK, and ZK Khan.
Patent # 1127/DEL/92,1992.
"A process for the preparation of 7-bromo-1-phenyl-8-acetoamido-9H-pyrido (3,4-b) indoles, useful as antifungal agents"
Agarwal A, Agarwal SK, Shukla PK, and ZK Khan.
Patent # 1126/Del/92,1992.
"A process for the preparation of 6-bromo-5-nitro-1-substituted-9H-pyrido (3,4-b) indoles useful as antifungal agents"
Agarwal A, Agarwal SK, Shukla PK, and ZK Khan.
Patent # 1123/DEL/92,1992.
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