Previous | Faculty Index | Next

Rice-Herrmann Web Site

Our major research interest is the regulation of gene expression during viral infection. Studies of viral gene regulation contribute to the understanding of important human pathogens and often lead to insight into general biological processes that have broad applicability to many areas of biology. During the past several years, we have largely focused on gene regulation during human immunodeficiency virus (HIV) infection. We have investigated the mechanism of action of the viral transcriptional activator protein known as Tat. Tat is unusual among transcriptional activator proteins in that it is targeted to cellular RNA polymerase II through binding to a promoter-proximal RNA element known as TAR, where it then acts to greatly stimulate transcriptional elongation of the integrated HIV provirus. We have obtained evidence that in order to activate transcription elongation, Tat targets the carboxyl terminal domain (CTD) of the largest subunit of RNA polymerase II for modification by phosphorylation. It is believed that CTD phosphorylation activates transcription by stimulating the promoter clearance of transcription complexes and/or converting elongation-deficient transcription complexes to highly processive complexes.

Several years ago, we identified a cellular serine/threonine protein kinase, now termed TAK/P-TEFb, that is the crucial co-factor that the Tat protein binds to, resulting in phosphorylation of the CTD and the subsequent activation of transcription of the viral genome. TAK/P-TEFb is known to be composed of at least two subunits - Cdk9 is the catalytic subunit and cyclin T1 is a regulatory subunit. Our current studies include further investigation of the molecular mechanisms involved in TAK/P-TEFb and Tat function. We are particularly interested in investigating the normal cellular roles and regulation of TAK/P-TEFb in cell types relevant to HIV infection. We are hopeful that our future studies will contribute to the understanding of fundamental principles of gene regulation in both viral and cellular systems.           

Given the laboratory’s long standing interest in host-cell interactions, we have recently initiated a project to identify cellular proteins that play a role in the pathogenesis of avian influenza virus infection.  Highly virulent strains of H5N1 avian influenza viruses are currently circulating in birds in Asia, Europe, and Africa.  The NS1 protein of avian viruses has recently been shown to be associated with virulence.  A critical feature of the avian NS1 protein is the presence of a protein domain at its carboxyl terminus termed the PDZ-ligand domain.  This domain was predicted to associate with cellular PDZ proteins, a large class of proteins that are typically involved in cell-cell contact and cellular migration.  It is notable that H5N1 viruses that have recently infected humans with an approximate 50% mortality rate express an NS1 protein with the PDZ-ligand domain.  The goal of our avian influenza project is to identify cellular PDZ proteins that are targeted by the NS1 PDZ-ligand domain.  With the identity of these PDZ proteins, we will investigate the functional consequence of their interaction with the avian influenza virus NS1 protein.  Additionally, we will attempt to derive small molecules that can inhibit the interaction between the NS1 protein and its cellular PDZ protein targets, as such small molecules may be the basis for the development of novel therapeutics to treat avian influenza virus infection

.Rice-Herrmann Web Site

Recent Publications (PubMed)

Ghose, R., Liou, L.-Y., Herrmann, C.H., and Rice, A.P.  (2001) Induction of TAK (cyclin T1-P-TEFb) in purified resting CD4+ T lymphocytes by combination of cytokines.  J. Virol.  75:11336-11343.

Liou, L.-Y., Herrmann, C.H., and Rice, A.P.  (2002). Transient induction of cyclin T1 during human monocytes differentiation regulates HIV-1 Tat transactivation function.  J. Virol.  76:  10579-10587.

Liu, H., Yu, Wendong, Liou, L.-Y., and Rice, A.P.  (2003). Isolation and characterization of the human DC-SIGN and DC-SIGNR promoters.  Gene.  313:  149-159.

Liou, L.-Y., Herrmann, C.H., and Rice, A.P.  (2004). HIV-1 infection induces cyclin T1 expression in macrophages.  J. Virol.  78:  8144-8119.

Haaland, R.E., Herrmann, C.H., and Rice, A.P.  (2005).  siRNA depletion of 7SK snRNA induces apoptosis but does not affect expression of the HIV-1 LTR or P-TEFb-dependent cellular genes.  J. Cell. Physiol.  205:463-470.

Wang, Y. and Rice, A.P.  (2006)  Interleukin-10 inhibits HIV-1 replication in human macrophages through the induction of cyclin T1 proteolysis.  Virology.  352:485-492.

Liu, H., Dow, E.C., Arora, R., Kimata, J.T., Bull, L.M., Arduino, R.C., and Rice. A.P. 
(2006)  Integration of human immunodeficiency virus type 1 in untreated infection occurs preferentially within genes.  J. Virol. 80:7765-7768.

Yu, W., Wang, Y., Shaw, C., Qin, X.-F., and Rice, A.P.  (2006)  Induction of HIV-1 Tat co-factor cyclin T1 during monocyte differentiation is required for the regulated expression of a large portion of cellular mRNAs.  Retrovirology 3:32.