Raghavendar Reddy Thipparthi (ai7741)

Associate Professor/ Director of IM PhD/MS Program

Raghavendar Thipparthi, PhD., is Associate Professor in the Department of Biochemistry, Microbiology and Immunology. Dr. Thipparthi received his PhD from the University of Hyderabad, Hyderabad, India (1989). He was a visiting scientist (1989) at the Oak Ridge National Laboratory, Tennessee; Post-graduate researcher (1990 - 93), and Assistant Research Scientist (1994 - 2000) in Dr. Flossie Wong-Staal's lab, Department of Medicine, University of California, San Diego, CA. He joined the faculty in Immunology and Microbiology in November 2000.

 PhD: School of Life Sciences (Dept of Biochemistry), University of Hyderabad, India

Accepting new MS students in 2024: Yes (IM)
Accepting new PhD students in 2024: No

7213 Scott Hall

Post-transcriptional regulation of human immunodeficiency virus (HIV) gene expression

The human immunodeficiency virus -1 (HIV-1) differentially controls viral protein expression at the level of splicing as well as the nuclear export of incompletely spliced viral RNAs. The HIV-1 Rev protein, which shuttles between the nucleus and cytoplasm, facilitates the nuclear export of unspliced mRNAs containing the Rev response element (RRE). This process, mediated by the Rev/RRE, interfaces with cellular components involved in the post-transcriptional gene regulation. Several cellular proteins that bind Rev and/or RRE have been identified, which either positively or negatively modulate Rev function. However, no cellular counterpart of Rev has been reported. We identified that a cellular protein, Sam68, can functionally substitute as well as synergize with Rev in RRE-mediated gene expression and virus production. Furthermore, we demonstrated that Sam68 is absolutely required for Rev function and HIV-1 production. The mechanism by which Sam68 enhances HIV-1 production is under investigation.

Another area of our lab focus is to understand the role of Rev in viral latency in astrocytes. Astrocytes serve as reservoirs and HIV preferentially establishes latency in these cells, partly due to mis-localization of Rev (cytoplasm) in these cells and contributes to functional block. Our hypothesis is that astrocytes express cytoplasmic protein(s) which interfere with the nuclear uptake of Rev, thus blocking the Rev function. One such protein is Hsp22, expressed at high levels in the cytoplasm of astrocytes. Currently, the role of Hsp22 in the Rev function and HIV-1 production in astrocytes is under investigation.

• Modem S, Dicarlo SE, Reddy TR. Fresh Garlic Extract Induces Growth Arrest and Morphological Differentiation of MCF7 Breast Cancer Cells. Genes Cancer. 3:177-86. 2012. Medline
• Modem S, Chinnakannu K, Bai U, Reddy GP, Reddy TR. Hsp22 (HspB8/H11) knockdown induces Sam68 expression and stimulates proliferation of glioblastoma cells. J Cell Physiol. 226:2747-51. 2011. Medline
• Suhasini M, Reddy TR. Cellular proteins and HIV-1 Rev function. Curr HIV Res. 7:91-100. 2009 Medline
• Modem S, Reddy TR. An anti-apoptotic protein, Hax-1, inhibits the HIV-1 rev function by altering its sub-cellular localization. J Cell Physiol. 2008 214:14-9. 2008. Medline
• Bagchi M, Besser D, Reddy TR, Skoff R, Maisel H. Effect of thermal stress on early and late passaged mouse lens epithelial cells. J Cell Biochem. 102:1036-42. 2007 Medline
• Badri KR, Modem S, Gerard HC, Khan I, Bagchi M, Hudson AP, Reddy TR. Regulation of Sam68 activity by small heat shock protein 22. J Cell Biochem. 99:1353-62. 2006. Medline
• Singh K.P., Gerard H.C., Hudson A.P., Reddy T.R., Boros D.L. Retroviral Foxp3 gene transfer ameliorates liver granuloma pathology in Schistosoma mansoni infected mice. Immunology, 114:410-417, 2005. Medline
• Modem S., Badri K.R., Holland T.C., Reddy T.R. Sam68 is absolutely required for Rev function and HIV-1 production. Nucleic Acids Res., 33:873-879, 2005. Medline
• Yang J.P., Reddy T.R., Truong K.T., Suhasini M., Wong-Staal F. Functional interaction of Sam68 and heterogeneous nuclear ribonucleoprotein K. Oncogene, 21:7187-7194, 2002. Medline
• Xu W., Zhang Y., Yeh L.Y., Ruprecht C.R., Wong-Staal F., McFadden B.A., Reddy T.R., Ruprecht R.M. One-step, highly efficient site-directed mutagenesis by toxic protein selection. Biotechniques, 32:1266-1268, 1270, 2002. Medline
• Reddy T.R., Suhasini M., Xu W., Yeh L.Y., Yang J.P., Wu J., Artzt K., Wong-Staal F. A role for KH domain proteins (Sam68-like mammalian proteins and quaking proteins) in the post-transcriptional regulation of HIV replication. J. Biol. Chem., 277:5778-5784, 2002. Medline
• Yang, J-P., Tang, H., Reddy, T. R., and Wong-Staal, F. (2001). Mapping the functional domains of HAP95, a protein that binds RNA helicase A and activates the constitutive transport element of type-D retroviruses. J. Biol. Chem., 276:30694-30700, 2001. Medline
• Reddy, T. R., Xu, W., and Wong-Staal. F. (2000). General effect of Sam68 on Rev/Rex regulated expression of complex retroviruses. Oncogene 19:4071-4074. Medline
• Reddy, T. R., Tang, H., Xu, W., and Wong-Staal. F. (2000). Sam68, RNA helicase A and Tap co-operate in the post-transcriptional regulation of retroviral mRNA. Oncogene 19:3570-3575. Medline
• Reddy, T. R. (2000). A single point mutation in the nuclear localization signal (NLS) of Sam68 blocks the Rev/RRE-mediated post-transcriptional regulation of HIV-1. Oncogene 19:3110-3114. Medline
• Westberg, C., Yang, J-P., Tang, H., Reddy, T. R., and Wong-Staal, F. (2000). A novel shuttle protein binds to RNA helicase A and activates the retroviral constitutive transport element. J. Biol. Chem. 275:21396-21401. Medline

Raghavendar Thipparthi (T.R. Reddy), Ph.D., is Associate Professor in the Department of Immunology and Microbiology. Dr. Reddy received his Ph.D. from the University of Hyderabad, Hyderabad, India in 1989. He was a visiting scientist (1989) at Oak Ridge National Laboratory, Tennessee; Post-graduate researcher (1990 - 93) and Assistant Research Scientist (1994 - 2000) in Dr. Wong-Staal's lab in the Department of Medicine at the University of California, San Diego. He joined the faculty in Immunology and Microbiology in November 2000.

Dr. Reddy's research interests include understanding the role of cellular proteins in the post-transcriptional regulation of human immunodeficiency virus (HIV). The Rev protein of human immunodeficiency virus (HIV) facilitates the nuclear export of unspliced or singly spliced viral mRNA. Rev has been shown to be a shuttle protein, comprised of a basic, nuclear localization sequence and a leucine-rich nuclear export sequence (NES). Rev specifically interacts with the cognate target sequence, RRE. Several cellular proteins that bind Rev and/or RRE have been identified, which either positively or negatively modulate Rev activity. However, no cellular counterpart of Rev has been reported. Recently, he has identified that a cellular protein, Sam68, can functionally substitute as well as synergize with Rev in RRE mediated gene expression and virus replication. Sam68 is a member of the KH domain family proteins. Carboxy-terminal deletion or point mutants of Sam68 inhibit the transactivation of RRE-mediated gene expression by both wild-type Sam68 and Rev.

The laboratory is currently focusing on the functional relevance of Sam68 in HIV replication: (i) to explore if Rev is functional without Sam68 in RRE-directed transactivation using (a) anti-sense Sam68 and (b) ribozyme gene expression knockout as a means to evaluate the functional relevance of Sam68 implicated in Rev-mediated transactivation; (ii) to generate an in vitro model for the enhancement of HIV-1 replication in NIH3T3 cells by Sam68; (iii) to assess the long-term protection of primary cells expressing transdominant negative mutants of Sam68 from HIV infection; (iv) to explore whether other KH family proteins also substitute for Rev function in HIV replication and (v) to decipher the Sam68-mediated RNA export pathway. A second area of interest of Dr. Reddy's laboratoty is to investigate the role of HTLV Tax in the development of neurological disorder, namely, Tropical Spastic Parapheresis (TSP). The Human T-cell Leukemia Virus (HTLV) is associated with adult T-cell leukemia and neurological disorders (TSP/HAM). The HTLV transcriptional transactivator, Tax, is known to exert its effect through protein-protein interaction with several transcription factors that activate genes in T-cell proliferation. The pathogenic mechanism in the CNS is less defined. In connection with TSP/HAM diseases, using the yeast two-hybrid system, Dr. Reddy has identified and characterized a cDNA clone corresponding to a human neuronal intermediate filament protein a-internexin. We are currently investigating: i) the in vivo assembly and co-assembly of neuronal intermediate filaments in the presence of extra-cellular and exogenously expressed Tax in neuronal cells, and ii) to identify and characterize additional cellular proteins that interact with Tax and are pertinent to TSP/HAM disease.

• Modem S, Dicarlo SE, Reddy TR. Fresh Garlic Extract Induces Growth Arrest and Morphological Differentiation of MCF7 Breast Cancer Cells. Genes Cancer. 3:177-86. 2012. Medline
• Modem S, Chinnakannu K, Bai U, Reddy GP, Reddy TR. Hsp22 (HspB8/H11) knockdown induces Sam68 expression and stimulates proliferation of glioblastoma cells. J Cell Physiol. 226:2747-51. 2011. Medline
• Suhasini M, Reddy TR. Cellular proteins and HIV-1 Rev function. Curr HIV Res. 7:91-100. 2009 Medline
• Modem S, Reddy TR. An anti-apoptotic protein, Hax-1, inhibits the HIV-1 rev function by altering its sub-cellular localization. J Cell Physiol. 2008 214:14-9. 2008. Medline
• Bagchi M, Besser D, Reddy TR, Skoff R, Maisel H. Effect of thermal stress on early and late passaged mouse lens epithelial cells. J Cell Biochem. 102:1036-42. 2007 Medline
• Badri KR, Modem S, Gerard HC, Khan I, Bagchi M, Hudson AP, Reddy TR. Regulation of Sam68 activity by small heat shock protein 22. J Cell Biochem. 99:1353-62. 2006. Medline
• Singh K.P., Gerard H.C., Hudson A.P., Reddy T.R., Boros D.L. Retroviral Foxp3 gene transfer ameliorates liver granuloma pathology in Schistosoma mansoni infected mice. Immunology, 114:410-417, 2005. Medline
• Modem S., Badri K.R., Holland T.C., Reddy T.R. Sam68 is absolutely required for Rev function and HIV-1 production. Nucleic Acids Res., 33:873-879, 2005. Medline
• Yang J.P., Reddy T.R., Truong K.T., Suhasini M., Wong-Staal F. Functional interaction of Sam68 and heterogeneous nuclear ribonucleoprotein K. Oncogene, 21:7187-7194, 2002. Medline
• Xu W., Zhang Y., Yeh L.Y., Ruprecht C.R., Wong-Staal F., McFadden B.A., Reddy T.R., Ruprecht R.M. One-step, highly efficient site-directed mutagenesis by toxic protein selection. Biotechniques, 32:1266-1268, 1270, 2002. Medline
• Reddy T.R., Suhasini M., Xu W., Yeh L.Y., Yang J.P., Wu J., Artzt K., Wong-Staal F. A role for KH domain proteins (Sam68-like mammalian proteins and quaking proteins) in the post-transcriptional regulation of HIV replication. J. Biol. Chem., 277:5778-5784, 2002. Medline
• Yang, J-P., Tang, H., Reddy, T. R., and Wong-Staal, F. (2001). Mapping the functional domains of HAP95, a protein that binds RNA helicase A and activates the constitutive transport element of type-D retroviruses. J. Biol. Chem., 276:30694-30700, 2001. Medline
• Reddy, T. R., Xu, W., and Wong-Staal. F. (2000). General effect of Sam68 on Rev/Rex regulated expression of complex retroviruses. Oncogene 19:4071-4074. Medline
• Reddy, T. R., Tang, H., Xu, W., and Wong-Staal. F. (2000). Sam68, RNA helicase A and Tap co-operate in the post-transcriptional regulation of retroviral mRNA. Oncogene 19:3570-3575. Medline
• Reddy, T. R. (2000). A single point mutation in the nuclear localization signal (NLS) of Sam68 blocks the Rev/RRE-mediated post-transcriptional regulation of HIV-1. Oncogene 19:3110-3114. Medline
• Westberg, C., Yang, J-P., Tang, H., Reddy, T. R., and Wong-Staal, F. (2000). A novel shuttle protein binds to RNA helicase A and activates the retroviral constitutive transport element. J. Biol. Chem. 275:21396-21401. Medline

Role of Sam68 in HIV-1 infection