Dr. Jagannadha K. Sastry
The University of Texas MD Anderson Cancer Center
Department of Immunology
- HIV vaccine development
- Mucosal epithelial cells in HIV-1 infection
- Biomarkers and therapeutic vaccine candidates for HPV-associated neoplasia
Our research program in the broad areas of viral oncology and immunology focuses on understanding the biology, pathology, immunology, and genetics of two viral diseases impacting human health: human immunodeficiency virus (HIV) infection that causes acquired immunodeficiency syndrome (AIDS) and human papillomavirus (HPV) infection associated with genital cancers like the cervical cancer and others like the oropharyngeal cancers. The overall goal of our research is to develop procedures and reagents for prediction, treatment as well as prevention of these human infectious immune disorders. We specialize in developing synthetic peptide-based vaccines and therapeutics that offer the advantage of being defined, safe and economical. Major areas of current research in the laboratory are:
Development of biomarkers and therapeutic vaccine candidates for HPV-associated cancers and pre-cancerous lesions: Two currently approved HPV vaccines prevent human papillomavirus (HPV) infection and development of cervical neoplasia in young females, but these prophylactic vaccines based on viral L1 protein are unsuitable for the treatment of existing HPV+ dysplasia and cancers that express viral E6 and E7 oncogenes but not the L1 gene. In collaboration with clinical colleagues from gynecologic oncology we have established that cellular immune responses specific to certain synthetic peptides corresponding to the E6 and E7 oncogenes of high-risk HPV correlate with recovery and disease-free condition in HPV+ patients treated for pre-cancerous cervical lesions. These HPV peptides can potentially serve as prognostic biomarkers and candidates for immunotherapeutic vaccination against recurrence as well as prevent progression of HPV-associated pre-cancerous cervical lesions. Nasal delivery of these E6 and E7 peptides effectively prevented HPV tumor development as well as regression of established HPV tumors in a mouse model. Current major focus is to design these vaccine peptides with adjuvants suitable for safe and effective delivery to mucosal tissues.
Design synthetic peptide cocktail HIV vaccine: Our laboratory developed a synthetic peptide-cocktail vaccine based on highly conserved sequences within the envelope protein of HIV-1 that proved effective against AIDS development after pathogenic virus challenge in a series of studies conducted in non-human primates (rhesus macaques of Indian origin) from the SPF breeding colony at our institutional primate facility in Bastrop, Texas. In these studies, we took advantage of the extraordinary capacity of dendritic cells (DC) as potent antigen presenting cells, to deliver the vaccine peptide cocktail to monkeys for the observed efficacy. Since HIV is mainly transmitted in humans by the vaginal/rectal mucosal routes, we are currently testing strategies to induce protective immune responses at these sites by effectively delivering this HIV peptide-cocktail vaccine along with suitable adjuvants to induce immunity at the oro-genital mucosal sites in a manner suitable for human use.
Determining the role of mucosal epithelial cells in HIV-1 infection: The predominant mode of HIV transmission worldwide is infection across the vaginal, rectal and oral mucosal tissues. However, the mucosal epithelial cells do not express receptors for HIV and the mucosal microenvironment is laden with soluble antiviral factors. Thus, an unsolved question is the identity and role of the first cell type within the mucosa to sense HIV, trigger immune activation, and promote HIV infection and spread. We discovered that HIV can induce human genital epithelial cells to produce a cytokine called thymic stromal lymphopoietin (TSLP) via the NF?B signaling pathway and the TSLP, through activating DC, promoted robust increase in local CD4+ T cells for efficient infection and systemic spread of HIV. In rhesus macaques inoculated with simian immunodeficiency virus (SIV) by the vaginal route we observed dramatic increases in TSLP expression, accumulation of DC and CD4+ T cells, and enhanced SIV replication, in the vaginal tissues within the first two weeks after virus exposure. These studies provide new and important clues for HIV invasion across genital mucosa and identify novel targets for prophylactic and therapeutic interventions including development of microbicides.
A tutorial in my laboratory will provide experience in immunology related to cancer and viruses, and research techniques employing mouse models as well as samples from rhesus macaques, chimpanzees, and humans for T cells assays including polychromatic flowcytometric analyses of phenotype and antigen-specific functional activities of different cell subsets, immunoprecipitations, ELISA, ELISPOT, western blotting, and immunizations in mice employing parenteral and mucosal routes, etc. Students will have the opportunity to get first-hand experience in translating research from the laboratory to humans for developing products against HIV and HPV.
Manuriet RM et al. Intranasal immunization with synthetic peptides corresponding to the E6 and E7 oncoproteins of human papillomavirus type 16 induces systemic and mucosal cellular immune responses and tumor protection. Vaccine 25:3304, 2007
Nehete PN et al. Selective induction of cell-mediated immunity and protection of rhesus macaques from chronic SHIV(KU2) infection by prophylactic vaccination with a conserved HIV-1 envelope peptide-cocktail. Virology 370:130, 2008
Courtney AN et al. Alpha-Galactosylceramide is an effective mucosal adjuvant for repeated intranasal or oral delivery of HIV peptide antigens. Vaccine, 27:3335-41, 2009
Fontenot DR et al. TSLP production by epithelial cells exposed to immunodeficiency virus triggers DC-mediated mucosal infection of CD+ T cells. Proc NatlAcdSci, USA (In Press) 2009
Weaver, EA et al: Comparison of replication-competent first generation, and helper-dependent adenoviral vaccines; PlosOne 4(3): e5059, 2009
He H et al: Multicolor flow cytometry analyses of cellular immune responses in macaques. J Vis Exp. 2010 Apr 22;(38). pii: 1743. doi: 10.3791/1743, PMID: 20414189
He H, et al: Functional impairment of central memory CD4 T cells is a potential early prognostic marker for changing viral load in SHIV-infected rhesus macaques. PLoS One. 2011;6(5):e19607
Courtney AN, et al: Intranasal but not intravenous delivery of the adjuvant alpha-galactosylceramide permits repeated stimulation of natural killer T cells in the lung. Eur. J. Immunol. 2011 (In Press)
Office: MDA SCR4.2013 (Unit 902)
Ph.D. - National Dairy Research Institute - 1981