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The
Battlefront of Severe Combined Immunodeficiencies (SCID): BLS and AIDS
We study the molecular biology of major histocompatibility complex class
II (MHCII) determinants and of the human immunodeficiency virus (HIV).
Defects in four transcription factors that regulate the expression of
MHCII genes result in the bare lymphocyte syndrome, which is an autosomal
recessive SCID. Affected children die early from superinfection. We characterized
lesions in three of these genes and identified recently the last gene
mutated in BLS. These findings will facilitate the prenatal diagnosis
as well as the genetic reconstitution and cure of the disease. Additional
insights into the regulation of MHCII genes allow us to manipulate the
immune response at will, leading to better immunotherapy of cancer, more
effective vaccination,and new models of organ-specific autoimmunity.
In the realm of AIDS, we characterized important steps in the replication
of HIV. To this end, we were the first to define transcriptional latency
and reservoir of the virus in infected individuals, which remains the
key obstacle to the cure of the disease. Moreover we pioneered specific
strategies to eliminate this reservoir. To this end, we also characterized
how the viral transactivator Tat activates the replication of HIV, by
increasing rates of elongation rather than initiation of transcription.
This new discovery then led to studies of this aspect of transcription,
which revealed that enhancers and silencers act from distal sites to activate
or repress the elongation of RNA polymerase II. Since Tat binds an RNA
structure called the transactivation response (TAR) element, we also characterized
other RNA-binding activators and the structure of the complex between
a cyclin-dependent kinase (CycT1:Cdk9), Tat and TAR in great molecular
detail. Finally, we study the mechanism of action of the viral negative
effector Nef, which plays a key role in the replication and infectivity
of HIV. By studying effects of Nef on the infected cell and progeny virions,
we characterized its mechanism of action. Information on these two key
viral proteins will lead to new therapies in AIDS.
Selected Publications:
Kao, SY, Calman, AF, Luciw, PA and Peterlin, BM. Anti-termination of transcription
within the long terminal repeat of HIV-1 by tat gene product. Nature 330
(1987): 489-493.
Selby, MJ and Peterlin, BM. Trans-activation by HIV-1 Tat via a heterlogous
RNA-binding protein. Cell 63 (1990): 769-776.
Cujec, T, Okamoto, Fujinaga, K, Meyer, JH, Chamberlin, H, Morgan, DO,
Peterlin, BM: The HIV trans-activator Tat binds to the CDK-activating
kinase (CAK) and activates the phosphorylation of the C-terminal domain
of RNA polymerase II. Genes and Development 11 (1997): 2645-2657.
Barboric, M., R. Nissen, S. Kanazawa, N. Jabrane-Ferrat, and B.M. Peterlin
2001. NF-kB Associates with P-TEFb to stimulate transcriptional elongation
by RNA Polymerase II. Mol. Cell 8:327-337.
Fackler, O.T., P. dÕAloja, A.S. Baur, M. Federico, and B.M. Peterlin.
2001. Nef from HIV-1F12 acts as a dominant negative inhibitor of virus
production and virion infectivity. J. Virol. 75:6601-8.
Nekrep, N., M. Geyer, and B.M. Peterlin. 2001. Analysis of ankyrin repeats
reveals how a single point mutation in RFXANK results in bare lymphocyte
syndrome. Mol. Cell. Biol. 21:5531-40.
Zheng, Y-H., A. Plemenitas, T. Linnemann, O.T. Fackler, and B.M. Peterlin.
2001. Nef increases infectivity of HIV via lipid rafts. Curr. Biol. 11:875-9.
Taube, R., X. Lin, D. Irwin, K. Fujinaga, and B.M.Peterlin. 2002. Interaction
between P-TEFb and C-terminal domain of RNA polymerase II activates transcription
from sites upstream and downstream of target genes. Mol. Cell. Biol. 22:321-331.
Contact Information:
Email: matija@itsa.ucsf.edu
Phone: 415/ 502-1905
Address: Box 0703, Room N 215
The University of California, San Francisco, CA 94143, (415) 476-9000
Copyright 2003, The Regents of the University of California.
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